Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

ABSTRACT

Inhibitors of HBV replication of Formula (ID) 
     
       
         
         
             
             
         
       
     
     including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, R a  to R d  and R 4  to R 6  have the meaning as defined herein. 
     The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.

BACKGROUND ART

The Hepatitis B virus (HBV) is an enveloped, partially double-strandedDNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). Itsgenome contains 4 overlapping reading frames: the precore/core gene; thepolymerase gene; the L, M, and S genes, which encode for the 3 envelopeproteins; and the X gene.

Upon infection, the partially double-stranded DNA genome (the relaxedcircular DNA; rcDNA) is converted to a covalently closed circular DNA(cccDNA) in the nucleus of the host cell and the viral mRNAs aretranscribed. Once encapsidated, the pregenomic RNA (pgRNA), which alsocodes for core protein and Pol, serves as the template for reversetranscription, which regenerates the partially dsDNA genome (rcDNA) inthe nucleocapsid.

HBV has caused epidemics in parts of Asia and Africa, and it is endemicin China. HBV has infected approximately 2 billion people worldwide ofwhich approximately 350 million people have developed chronicinfections. The virus causes the disease hepatitis B and chronicinfection is correlated with a strongly increased risk for thedevelopment cirrhosis and hepatocellular carcinoma.

Transmission of hepatitis B virus results from exposure to infectiousblood or body fluids, while viral DNA has been detected in the saliva,tears, and urine of chronic carriers with high titer DNA in serum.

An effective and well-tolerated vaccine exists, but direct treatmentoptions are currently limited to interferon and the followingantivirals; tenofovir, lamivudine, adefovir, entecavir and telbivudine.

In addition, heteroaryldihydropyrimidines (HAPs) were identified as aclass ofHBV inhibitors in tissue culture and animal models (Weber etal., Antiviral Res. 54: 69-78).

WO2013/006394, published on Jan. 10, 2013, relates to a subclass ofSulphamoyl-arylamides active against HBV. WO2013/096744, published onJun. 26, 2013 relates to compounds active against HBV.

In addition, WO2014/033170 and WO2014/033176, published on Mar. 6, 2014relate further compounds active against HBV.

Amongst the problems which HBV direct antivirals may encounter aretoxicity, mutagenicity, lack of selectivity, poor efficacy, poorbioavailability, and difficulty of synthesis.

There is a need for additional HBV inhibitors that may overcome at leastone of these disadvantages or that have additional advantages such asincreased potency or an increased safety window.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of Formula (ID)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN, C₁-C₃alkyl and        C₃-C₄cycloalkyl;    -   R^(d) is Hydrogen or Fluoro;    -   R⁴ is Hydrogen, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, —CN, Fluoro, Chloro, Bromo, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, C₁-C₃alkyl optionally substituted with        methoxy, C₂-C₃alkenyl or C₃-C₄cycloalkyl;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof        wherein such compound is not

The invention further relates to a pharmaceutical composition comprisinga compound of Formula (ID), and a pharmaceutically acceptable carrier.

The invention also relates to the compounds of Formula (ID) for use as amedicament, preferably for use in the prevention or treatment of an HBVinfection in a mammal.

In a further aspect, the invention relates to a combination of acompound of Formula (ID), and another HBV inhibitor.

The pharmaceutical composition, use and combination of compounds ofFormula (ID) as provided according to the present invention includes thepharmaceutical composition, use and combination of

Definitions

The terms “C_(1-x)alkyl” and C₁-C_(x)alkyl can be used interchangeably.

The term “C₁₋₃alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numberranging from 1 to 3. In case C₁₋₃alkyl is coupled to a further radical,it refers to a Formula C_(n)H_(2n). C₁₋₃alkyl groups comprise from 1 to3 carbon atoms, more preferably 1 to 2 carbon atoms. C₁₋₃alkyl includesall linear, or branched alkyl groups with between 1 and 3 carbon atoms,and thus includes such as for example methyl, ethyl, n-propyl, andi-propyl.

C₁₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as the group defined for C₁₋₃alkyl and butyl and the like.

C₁₋₆alkyl and C₂₋₆alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 6carbon atoms, or from 2 to 6 carbon atoms such as the groups defined forC₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like.

The term “C₂₋₃alkenyl” as a group or part of a group refers to ahydrocarbon radical comprising 2 or 3 carbon atoms having at least onedouble bond therein, and thus includes such as for example, ethenyl(vinyl), 1-propenyl, and 2-propenyl.

The term “C₁₋₃alkyloxy” as a group or part of a group refers to aradical having the Formula —OR^(c) wherein R^(c) is C₁₋₃alkyl.Non-limiting examples of suitable C₁₋₃alkyloxy include methyloxy (alsomethoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.

As used herein, the term “3-7 membered mono or polycyclic saturatedring” means saturated cyclic hydrocarbon with 3, 4, 5, 6 or 7 carbonatoms and is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl (monocyclic) and fused or spiro ring systems with 2 ormore saturated rings with at most 7 carbon atoms (polycyclic).

Such saturated ring optionally contains one or more heteroatoms, suchthat at least one carbon atom is replaced by a heteroatom selected fromN, O and S, in particular from N and O. Examples include oxetane,tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl,thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclichydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples includeoxetane, and tetrahydrofuranyl.

It should be noted that different isomers of the various heterocyclesmay exist within the definitions as used throughout the specification.For example, if not structurally specified according to the chemicalname or structure, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

The term halo and halogen are generic to Fluoro, Chloro, Bromo or Iodo.Preferred halogens are Bromo, Fluoro and Chloro.

It should also be noted that the radical positions on any molecularmoiety used in the definitions may be anywhere on such moiety as long asit is chemically stable. For instance pyridyl includes 2-pyridyl,3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and3-pentyl.

Positions indicated on phenyl (e.g. ortho, meta and/or para) areindicated relative to the bond connecting the phenyl to the mainstructure. An example with regard to the position of para R² location isindicated relative to the nitrogen (*) connected to the main structure:

When any variable (e.g. halogen or C₁₋₄alkyl) occurs more than one timein any constituent, each definition is independent.

For therapeutic use, the salts of the compounds of Formula (ID) arethose wherein the counter ion is pharmaceutically or physiologicallyacceptable. However, salts having a pharmaceutically unacceptablecounter ion may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound of Formula (ID).All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

The pharmaceutically acceptable or physiologically tolerable additionsalt forms which the compounds of the present invention are able to formcan conveniently be prepared using the appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, aspartic,dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said acid addition salt forms can be converted by treatmentwith an appropriate base into the free base form.

The term “salts” also comprises the hydrates and the solvent additionforms that the compounds of the present invention are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The present compounds may also exist in their tautomeric forms Forexample, tautomeric forms of amide (—C(═O)—NH—) groups are iminoalcohols(—C(OH)═N—). Tautomeric forms, although not explicitly indicated in thestructural formulae represented herein, are intended to be includedwithin the scope of the present invention.

The term stereochemically isomeric forms of compounds of the presentinvention, as used hereinbefore, defines all possible compounds made upof the same atoms bonded by the same sequence of bonds but havingdifferent three-dimensional structures which are not interchangeable,which the compounds of the present invention may possess. Unlessotherwise mentioned or indicated, the chemical designation of a compoundencompasses the mixture of all possible stereochemically isomeric formswhich said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe present invention both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term‘stereoisomerically pure’ concerns compounds or intermediates having astereoisomeric excess of at least 80% (i. e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms ‘enantiomerically pure’ and‘diastereomerically pure’ should be understood in a similar way, butthen having regard to the enantiomeric excess, respectively thediastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric forms of Formula (ID) can be obtained separately byconventional methods. Appropriate physical separation methods that mayadvantageously be employed are, for example, selective crystallizationand chromatography, e.g. column chromatography.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of Hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

DETAILED DESCRIPTION OF THE INVENTION

Whenever used hereinafter, the term “compounds of formula (ID)”,

or “the present compounds” “compounds of the present invention” orsimilar term is meant to include the compounds of general formula (ID),(IA), (IB), (IC), (I), (Ia), (II), (III) salts, stereoisomeric forms andracemic mixtures or any subgroups thereof.

In a first aspect, the present invention relates to a compound ofFormula (ID)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN, C₁-C₃alkyl and        C₃-C₄cycloalkyl;    -   R^(d) is Hydrogen or Fluoro;    -   R⁴ is Hydrogen, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, —CN, Fluoro, Chloro, Bromo, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, C₁-C₃alkyl optionally substituted with        methoxy, C₂-C₃alkenyl or C₃-C₄cycloalkyl;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof        wherein such compound is not

In a further aspect, aspect, the present invention relates to a compoundof Formula (IA)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN, C₁-C₃alkyl and        C₃-C₄cycloalkyl;    -   R⁴ is Hydrogen, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, —CN, Fluoro, Chloro, Bromo, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof,        wherein such compound is

-   -   In one embodiment, the present invention relates to a compound        Formula (IC)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   X represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN, C₁-C₃alkyl and        C₃-C₄cycloalkyl;    -   R⁴ is Hydrogen, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, —CN, Fluoro, Chloro, Bromo, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, C₁-C₃alkyl or C₃-C₄cycloalkyl;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof,        wherein such compound is

Of interest are compounds of the present invention wherein:

-   -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN, and C₁-C₃alkyl;    -   R⁴ is Hydrogen, or methyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl and a 3-7        membered saturated ring optionally containing one or more        heteroatoms each independently selected from the group        consisting of O, S and N, such 3-7 membered saturated ring or        C₂-C₆alkyl optionally being substituted with one or more        substituents each independently selected from the group        consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and C₁-C₄alkyl        optionally substituted with R¹⁰.    -   R⁷ represents hydrogen, —CN, Fluoro, Chloro, Bromo, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃ or methyl;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl.

Another embodiment of the present invention relates to those compoundsof Formula (ID), (IA) or any subgroup thereof as mentioned in any of theother embodiments wherein one or more of the following restrictionsapply:

-   -   (a) R⁴ is C₁-C₃alkyl, preferably methyl; R⁶ is selected from the        group consisting of C₂-C₆alkyl optionally being substituted with        one or more Fluoro; and R⁷ represents hydrogen Fluoro, Chloro or        C₁-C₃alkyl, preferably hydrogen Fluoro, Chloro or methyl.    -   (b) R^(b) is Hydrogen or Fluoro.    -   (c) R^(a) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Chloro —CN and methyl.    -   (d) R^(b) is Hydrogen or Fluoro and R^(a) and R^(c) are        independently selected from the group consisting of Hydrogen,        Fluoro, Chloro and —CN.    -   (e) R⁶ contains a 3-7 membered saturated ring optionally        containing one oxygen, more specifically R⁶ is a 4 or 5 membered        saturated ring containing one oxygen, such 4 or 5 membered        saturated ring optionally substituted with C₁-C₄alkyl optionally        substituted with R¹⁰.    -   (f) R⁶ comprises a branched C₃-C₆alkyl optionally substituted        with one or more Fluoro, or wherein R⁶ comprises a        C₃-C₆cycloalkyl wherein such C₃-C₆cycloalkyl is substituted with        one or more Fluoro or substituted with C₁-C₄alkyl substituted        with one or more Fluoro, or wherein R⁶ comprises a        C₃-C₆cycloalkyl optionally substituted with one or more Fluoro        and/or substituted with C₁-C₄alkyl optionally substituted with        one or more Fluoro.    -   (g) R⁶ comprises a branched C₃-C₆alkyl optionally substituted        with one or more Fluoro, or R⁶ comprises a C₃-C₆cycloalkyl        wherein such C₃-C₆cycloalkyl is substituted with one or more        Fluoro or substituted with C₁-C₄ substituted with one or more        Fluoro. More specifically, R⁶ is a branched C₃-C₆alkyl        substituted with one or more Fluoro.    -   (h) R⁴ is C₁-C₃alkyl, preferably methyl; R⁶ is selected from the        group consisting of C₂-C₆alkyl optionally being substituted with        one or more Fluoro; and R⁷ represents hydrogen, Fluoro, Chloro        or C₁-C₃alkyl, preferably hydrogen Fluoro, Chloro or methyl.

In one aspect, the present invention relates to a compound of Formula(IA)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN and methyl;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, CN, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof,        wherein such compound is not

In a further aspect, the present invention relates to a compound ofFormula (IA)

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN and methyl;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof,        wherein such compound is not

In a further aspect, the invention relates to compound of Formula

-   -   or a stereoisomer or tautomeric form thereof, wherein:    -   Each X independently represents CR⁷;    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂,        —CF₂-methyl, —CH₂F, —CF₃, —OCF₃, —CN and methyl;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered mono or polycyclic saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and        C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;    -   or a pharmaceutically acceptable salt or a solvate thereof,    -   wherein such compound is not

In one embodiment of compounds of the present invention, R⁴ is methyl.

In a further embodiment of compounds of the present invention, R^(b) isHydrogen or Fluoro. Furthermore, compounds according to the inventionare described wherein R^(a) and R^(c) are independently selected fromthe group consisting of Hydrogen, Fluoro, Chloro —CN and methyl.Preferably, R^(b) is Hydrogen or Fluoro and R^(a) and R^(c) areindependently selected from the group consisting of Hydrogen, Fluoro,Chloro and —CN.

In one embodiment of compounds of the present invention, R⁶ is selectedfrom the group consisting of C₂-C₆alkyl, C₁-C₄alkyl-R⁸ optionallysubstituted with one or more Fluoro, C₁-C₄alkyl-R⁹ optionallysubstituted with one or more Fluoro, and a 3-7 membered saturated ringoptionally containing one or more heteroatoms each independentlyselected from the group consisting of O, S and N, such 3-7 memberedsaturated ring or C₂-C₆alkyl optionally being substituted with one ormore substituents each independently selected from the group consistingof Hydrogen, —OH, Fluoro, oxo, R⁹, R¹⁰ and C₁-C₄alkyl optionallysubstituted with R¹⁰. In a further embodiment, R⁶ contains a 3-7membered saturated ring optionally containing one oxygen, morespecifically R⁶ is a 5 membered saturated ring containing one oxygen,such 5 membered saturated ring optionally substituted with C₁-C₄alkyloptionally substituted with R¹⁰.

In one embodiment of compounds of the present invention, R⁶ comprises abranched C₃-C₆alkyl optionally substituted with one or more Fluoro, orR⁶ comprises a C₃-C₆cycloalkyl wherein such C₃-C₆cycloalkyl issubstituted with one or more Fluoro or substituted with C₁-C₄substituted with one or more Fluoro. More specifically, R⁶ is a branchedC₃-C₆alkyl substituted with one or more Fluoro.

In a further aspect, the invention provides compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

-   -   Each X independently represents CR⁷;    -   R² is Hydrogen, CN, Chloro or Fluoro;    -   R¹ and R³ are independently selected from the group consisting        of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂, —CH₂F, —CF₃, —OCF₃,        —CN and methyl, wherein at maximum one of R¹R² and R³ is        Hydrogen if one of R¹ and R³ is Chloro or —OCF₃;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸ optionally substituted with one or more Fluoro,        C₁-C₄alkyl-R⁹ optionally substituted with one or more Fluoro,        and a 3-7 membered saturated ring optionally containing one or        more heteroatoms each independently selected from the group        consisting of O, S and N, such 3-7 membered saturated ring or        —C₂-C₆alkyl optionally being substituted with one or more        substituents each independently selected from the group        consisting of Hydrogen, —OH, Fluoro, oxo and C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents, C₁-C₄alkyloxy, —SO₂-methyl, —C(═O)—OR¹¹ or        —C(═O)—N(R¹¹)₂    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;

or a pharmaceutically acceptable salt or a solvate thereof.

In one embodiment, compounds of Formula (I) are disclosed wherein:

-   -   Each X independently represents CR⁷;    -   R² is Hydrogen, CN, or Fluoro;    -   R¹ and R³ are independently selected from the group consisting        of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂, —CH₂F, —CF₃, —CN and        methyl, wherein at maximum one of R¹R² and R³ is Hydrogen if one        of R¹ and R³ is Chloro;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸, C₁-C₄alkyl-R⁹ and a 3-7 membered saturated ring        optionally containing one or more heteroatoms each independently        selected from the group consisting of O, S and N, such 3-7        membered saturated ring or —C₂-C₆alkyl optionally being        substituted with one or more substituents each independently        selected from the group consisting of Hydrogen, —OH, Fluoro, oxo        and C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents —C(═O)—OR¹¹ or —C(═O)—N(R¹¹)₂;    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃; and    -   R¹¹ represents hydrogen or C₁-C₃alkyl.

In one further embodiment, compounds of Formula (I) are disclosedwherein:

-   -   Each X independently represents CR⁷;    -   R² is Hydrogen or Fluoro;    -   R¹ and R³ are independently selected from the group consisting        of Hydrogen, Fluoro, Bromo, Chloro, CHF₂, CH₂F, CF₃ and methyl,        wherein at maximum one of R¹, R² and R³ is Hydrogen;    -   R⁴ is Hydrogen or methyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₃alkyl-R⁸ and a 3-7 membered saturated ring optionally        containing one or more heteroatoms each independently selected        from the group consisting of O, S and N, such 3-7 membered        saturated ring or C₂-C₆alkyl optionally being substituted with        one or more substituents each independently selected from the        group consisting of Hydrogen, OH, Fluoro, and C₁-C₄alkyl;    -   R⁷ represents Hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N.

In one embodiment, for compounds according to Formula (I), at least oneX represents CH.

In a further aspect, the invention provides compounds of Formula (Ia)

or a stereoisomer or tautomeric form thereof, wherein:

-   -   R² is Hydrogen, CN or Fluoro;    -   R¹ and R³ are independently selected from the group consisting        of Hydrogen, Fluoro, Bromo, Chloro, —CHF₂, —CH₂F, —CF₃, —CN and        methyl, wherein at maximum one of R¹, R² and R³ is Hydrogen if        one of R¹ and R³ is Chloro;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸, C₁-C₄alkyl-R⁹ and a 3-7 membered saturated ring        optionally containing one or more heteroatoms each independently        selected from the group consisting of O, S and N, such 3-7        membered saturated ring or —C₂-C₆alkyl optionally being        substituted with one or more substituents each independently        selected from the group consisting of Hydrogen, —OH, Fluoro, oxo        and C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents —C(═O)—OR¹¹ or —C(═O)—N(R¹¹)₂    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl;

or a pharmaceutically acceptable salts or a solvate thereof.

In a sub-embodiment, compounds of Formula (I) are disclosed wherein:

-   -   R² is Hydrogen or Fluoro;    -   R¹ and R³ are independently selected from the group consisting        of Hydrogen, Fluoro, CHF₂, CH₂F, CF₃ and methyl, wherein at        maximum one of R¹, R² and R³ is Hydrogen;    -   R⁴ is Hydrogen or methyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl and a 3-7        membered saturated ring optionally containing one or more        heteroatoms each independently selected from the group        consisting of O, S and N, such 3-7 membered saturated ring or        C₁-C₆alkyl optionally being substituted with one or more        substituents each independently selected from the group        consisting of Hydrogen, OH and C₁-C₄alkyl.

In another embodiment, compounds of the invention are represented byFormula (II)

In yet another embodiment, compounds of the invention are represented byFormula (III)

For both compounds of Formula (II) and (III):

-   -   R² is Hydrogen, CN or Fluoro;    -   R¹ is independently selected from the group consisting of        Fluoro, Bromo, Chloro, —CHF₂, —CH₂F, —CF₃, —CN and methyl,        wherein if R¹ is Chloro, R² is not Hydrogen;    -   R⁴ is Hydrogen or C₁-C₃alkyl;    -   R⁵ is Hydrogen;    -   R⁶ is selected from the group consisting of C₂-C₆alkyl,        C₁-C₄alkyl-R⁸, C₁-C₄alkyl-R⁹ and a 3-7 membered saturated ring        optionally containing one or more heteroatoms each independently        selected from the group consisting of O, S and N, such 3-7        membered saturated ring or —C₂-C₆alkyl optionally being        substituted with one or more substituents each independently        selected from the group consisting of Hydrogen, —OH, Fluoro, oxo        and C₁-C₄alkyl optionally substituted with R¹⁰;    -   R⁷ represents hydrogen, methyl, Fluoro or Chloro;    -   R⁸ represents 3-7 membered saturated ring optionally containing        one or more heteroatoms each independently selected from the        group consisting of O, S and N, such 3-7 membered saturated ring        optionally being substituted with one or more C₁-C₄alkyl        optionally substituted with R¹⁰;    -   R⁹ represents —C(═O)—OR¹¹ or —C(═O)—N(R¹¹)₂    -   R¹⁰ represents —CN, —OH, Fluoro, —CHF₂, —CH₂F or —CF₃;    -   R¹¹ represents hydrogen or C₁-C₃alkyl.

In one embodiment, compounds of the present invention are disclosedwherein R¹ is selected from either Bromo, Chloro, Fluoro or methyl, orFluoro or methyl. In another embodiment, R¹ is selected from eitherFluoro or methyl and at least one of R¹ and R³ is Fluoro. In yet afurther embodiment, R¹ is selected from either Fluoro or methyl and atleast one of R¹ and R³ is Fluoro, and the other R¹ or R³ is selectedfrom methyl, Fluoro, CHF₂, CH₂F, CF₃ and methyl. In another embodiment,at least two of R¹, R² and R³ are halogens, preferably Bromo, Fluoro orChloro, even more preferably Fluoro or Chloro. In a further embodiment,each of R¹, R² and R³ are halogen, preferably Bromo, Fluoro or Chloro,even more preferably Fluoro or Chloro.

In yet another embodiment, compounds of the present invention aredisclosed wherein R⁴ is methyl or ethyl, preferably methyl.

In a further embodiment, compounds of the present invention aredisclosed wherein R⁶ contains a 3-7 membered saturated ring optionallycontaining one oxygen, preferably R⁶ is a 5 membered saturated ringcontaining one oxygen.

In another embodiment, compounds of the present invention are disclosedwherein R⁶ comprises a C₁-C₄alkyl substituted with one or more Fluoro.In addition, compounds of the present invention are disclosed wherein R⁶comprises a branched C₃-C₆alkyl substituted with one or more Fluoro, orwherein R⁶ comprises a C₃-C₆cycloalkyl wherein such C₃-C₆cycloalkyl issubstituted with one or more Fluoro or substituted with C₁-C₄substituted with one or more Fluoro.

In yet another embodiment, compounds of the invention are disclosedwherein R⁶ comprises a carbon atom without hydrogen substituent.Preferably, carbon without hydrogen substituent is directly attached tothe Nitrogen of the —N—SO₂˜ moiety.

Further combinations of any of the embodiments are also envisioned to bein the scope of the present invention.

Preferred compounds according to the invention are compound or astereoisomer or tautomeric form thereof with a formula as represented inthe synthesis of compounds section and of which the activity isdisplayed in Table 1.

In a further aspect, the present invention concerns a pharmaceuticalcomposition comprising a therapeutically or prophylactically effectiveamount of a compound of Formula (ID) as specified herein, and apharmaceutically acceptable carrier. A prophylactically effective amountin this context is an amount sufficient to prevent HBV infection insubjects being at risk of being infected. A therapeutically effectiveamount in this context is an amount sufficient to stabilize HBVinfection, to reduce HBV infection, or to eradicate HBV infection, ininfected subjects. In still a further aspect, this invention relates toa process of preparing a pharmaceutical composition as specified herein,which comprises intimately mixing a pharmaceutically acceptable carrierwith a therapeutically or prophylactically effective amount of acompound of Formula (ID), as specified herein.

Therefore, the compounds of the present invention or any subgroupthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areemployed. For parenteral compositions, the carrier will usually comprisesterile water, at least in large part, though other ingredients, forexample, to aid solubility, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations intended to be converted, shortly beforeuse, to liquid form preparations. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin. The compounds of the present invention may also be administeredvia oral inhalation or insufflation in the form of a solution, asuspension or a dry powder using any art-known delivery system.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The compounds of Formula (ID) are active as inhibitors of the HBVreplication cycle and can be used in the treatment and prophylaxis ofHBV infection or diseases associated with HBV. The latter includeprogressive liver fibrosis, inflammation and necrosis leading tocirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, particularly their anti-HBVproperties, the compounds of Formula (ID) or any subgroup thereof, areuseful in the inhibition of the HBV replication cycle, in particular inthe treatment of warm-blooded animals, in particular humans, infectedwith HBV, and for the prophylaxis of HBV infections. The presentinvention furthermore relates to a method of treating a warm-bloodedanimal, in particular human, infected by HBV, or being at risk ofinfection by HBV, said method comprising the administration of atherapeutically effective amount of a compound of Formula (ID).

The compounds of Formula (ID), as specified herein, may therefore beused as a medicine, in particular as medicine to treat or prevent HBVinfection. Said use as a medicine or method of treatment comprises thesystemic administration to HBV infected subjects or to subjectssusceptible to HBV infection of an amount effective to combat theconditions associated with HBV infection or an amount effective toprevent HBV infection.

The present invention also relates to the use of the present compoundsin the manufacture of a medicament for the treatment or the preventionof HBV infection.

In general it is contemplated that an antiviral effective daily amountwould be from about 0.01 to about 50 mg/kg, or about 0.01 to about 30mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing about 1 to about 500 mg, or about 1 toabout 300 mg, or about 1 to about 100 mg, or about 2 to about 50 mg ofactive ingredient per unit dosage form.

The present invention also concerns combinations of a compound ofFormula (ID) or any subgroup thereof, as specified herein with otheranti-HBV agents. The term “combination” may relate to a product or kitcontaining (a) a compound of Formula (ID), as specified above, and (b)at least one other compound capable of treating HBV infection (hereindesignated as anti-HBV agent), as a combined preparation forsimultaneous, separate or sequential use in treatment of HBV infections.In an embodiment, the invention concerns combination of a compound ofFormula (ID) or any subgroup thereof with at least one anti-HBV agent.In a particular embodiment, the invention concerns combination of acompound of Formula (ID) or any subgroup thereof with at least twoanti-HBV agents. In a particular embodiment, the invention concernscombination of a compound of Formula (ID) or any subgroup thereof withat least three anti-HBV agents. In a particular embodiment, theinvention concerns combination of a compound of Formula (ID) or anysubgroup thereof with at least four anti-HBV agents.

The term anti-HBV agent also includes compounds capable of treating HBVinfection via immunomodulation. Examples of immunomodulators areinterferon-α (IFN-α), pegylated interferon-α or stimulants of the innateimmune system such as Toll-like receptor 7 and/or 8 agonists. Oneembodiment of the present invention relates to combinations of acompound of Formula (ID) or any subgroup thereof, as specified hereinwith an immunomodulating compound, more specifically a Toll-likereceptor 7 and/or 8 agonist.

The combination of previously known anti-HBV agents, such asinterferon-α (IFN-α), pegylated interferon-α, 3TC, adefovir or acombination thereof, and, a compound of Formula (ID) or any subgroupthereof can be used as a medicine in a combination therapy.

Generic Synthesis:

The substituents represented in this general synthesis section are meantto include any substituent or reactive species that is suitable fortransformation into any substituent according to the present inventionwithout undue burden for the person skilled in the art.

A possible synthesis of compound of general formula (I) is described inschemes 1 and 2. Similarly, the synthesis of compounds of generalformula (IA) are described in schemes 1a, 2a. Also similarly, thesynthesis of compounds of general formula ID is described in scheme 1band scheme 2b. A carboxylic acid chloride of general formula (IV) (forexample prepared according to the synthesis described for compound 2)can be selectively reacted with an aniline of general formula (V), forexample by slow addition of aniline (V) to a refluxing solution ofcompound (IV) in toluene, resulting in compound (VI). The remainingsulfonic acid chloride functionality in compound (VI) is further reactedwith an amine of general formula (VII), resulting in a compound ofgeneral formula (I), for example in a solvent like acetonitrile in thepresence of an inorganic base like sodium bicarbonate or as furtherexemplified in the experimental synthetic description of compounds.

Alternatively a compound of general formula (I) might be obtained asdescribed in scheme 2. This time the sulfonic acid chloride (VIII) (forexample prepared according to the synthesis described for compound 2) isreacted with an amine of general formula (VII), for example in anorganic solvent like CH₂Cl₂ in the presence of an organic base liketriethylamine or DIPEA. The formed compound (IX) is coupled with anilineof general formula (V) in the presence of an activating reagent like forexample HATU and an organic base like triethylamine or DIPEA.

An alternative method for the synthesis of compounds of general formulaIX, is via ester X as described in scheme 3. Reaction of X with amineVII, for example in an organic solvent like acetonitrile in the presenceof an organic base like for example triethylamine or DIPEA, or aninorganic base like for example sodium bicarbonate, resulting in acompound of general formula XI, followed by hydrolysis of the ester, forexample with LiOH in THF/H₂O, followed by acidification, results in acompound of general formula IX.

A compound of general formula VIII can be converted to a compound ofgeneral formula IV, for example by treatment with oxalyl chloride inCH₂Cl₂.

Possible synthetic routes, for compounds of general formula X and VIIIare described in scheme 4, and further exemplified in the experimentalsection. Chlorosulfonation of carboxylic ester XII or carboxylic acidXIII, can results in compounds of general formula X or VIIIrespectively, for example by treatment with chlorosulfonic acid at forexample 0° C., if necessary, followed by quenching with water.Alternatively, compound XII can be treated with chlorosulfonic acid,resulting in a sulfonic acid derivative, for example by treatment ofcompound XII with 1-1.2 equiv chlorosulfonic acid in CH₂Cl₂, theresulting sulfonic acid derivative can be converted the sulfonylchloride compound X, for example by treatment with SOCl₂ at 80° C.

Alternatively a compound of general formula (IA) might be obtained asdescribed in scheme 5. A compound of general formula XI can be coupledwith a compound of general formula Va in the presence of a base like forexample lithium bis(trimethylsilyl)amide, in a solvent like for exampleTHF, resulting in the formation of a compound of general formula (IA).Similarly, a compound of general formula ID can be prepared as describedin scheme 5a.

General Procedure LCMS Methods

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (R_(t))and ions. If not specified differently in the table of data, thereported molecular ion corresponds to the [M+H]⁺ (protonated molecule)and/or [M−H]⁻ (deprotonated molecule). In case the compound was notdirectly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺,[M+HCOO]⁻, etc.). All results were obtained with experimentaluncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” MassSelective Detector, “RT” room temperature, “BEH” bridgedethylsiloxane/silica hybrid, “DAD” Diode Array Detector, “HSS” HighStrength silica., “Q-Tof” Quadrupole Time-of-flight mass spectrometers,“CLND”, ChemiLuminescent Nitrogen Detector, “ELSD” Evaporative LightScanning Detector,

LCMS Methods

(Flow expressed in mL/min; column temperature (T) in ° C.; Run time inminutes).

Method Flow Run code Instrument Column Mobile phase Gradient Col T timeA Waters: Waters: A: 10 mM From 100% A 0.8 3.5 Acquity ® HSS A:CH₃COONH₄ to 5% A in 55 UPLC ®- T3 in 95% H₂O + 2.10 min, to 0% DAD and(1.8 μm, 5% CH₃CN A in 0.90 min SQD 2.1*100 B: CH₃CN to 5% A in mm) 0.5min B Waters: Waters: A: 10 mM From 95% A 0.8 2 Acquity ® BEH CH₃COONH₄to 5% A in 1.3 55 UPLC ®- C18 in 95% H₂O + min, held for DAD and (1.7μm, 5% CH₃CN 0.7 min. SQD 2.1*50 B: CH₃CN mm) C Waters: Waters: A: 10 mMFrom 95% A 0.8 3 Acquity ® HSS CH₃COONH₄ to 0% A in 55 UPLC ®- T3 in 95%H₂O + 2.5 min, to 5% DAD and (1.8 μm, 5% CH₃CN A in 0.05 min SQD 2.1*100B: CH₃CN mm) D Waters: Waters: A: 10 mM From 100% A 0.7 3.5 Acquity ®HSS CH₃COONH₄ to 5% A in 55 UPLC ®- T3 in 95% H₂O + 2.10 min, to 0% DADand (1.8 μm, 5% CH₃CN A in 0.90 min SQD 2.1*100 B: CH₃CN to 5% A in mm)0.5 min

Synthesis of Compounds:

Compound 1:N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)-1H-pyrrole-2-carboxamide

4-(isopropylsulfamoyl)-1H-Pyrrole-2-carboxylic acid (857 mg, 3.69 mmol),4-Fluoro-3-Methylaniline (461.8 mg, 369 mmol), COMU((1-Cyano-2-ethoxy-2-oxoethyliden-aminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate; CAS Number 1075198-30-9; 1738 mg, 4.06 mmol) andtriethylamine (2.0 mL, 4.06 mmol) in dichloromethane (43 mL) was stirredfor 3 hours. The reaction mixture was treated with 1M HCl (50 mL). Theprecipitate was filtered off and was recrystallized from hotacetonitrile (50 mL). The solid was filtered and dried overnight invacuo yielding a beige powder (58 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.00 (d, J=6.4 Hz, 6H), 2.23 (d, J=1.5 Hz, 3H), 3.20-3.31 (m, 1H),7.05-7.20 (m, 2H), 7.31-7.34 (m, 1H), 7.34-7.38 (m, 1H), 7.54-7.60 (m,1H), 7.62 (dd, J=7.2, 2.3 Hz, 1H), 10.01 (s, 1H), 12.33 (br. s., 1H).Method A; Rt: 1.51 min. m/z: 338.0 (M−H)⁻ Exact mass: 339.1.

Compound 2:N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

A mixture of 4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid(Commercial from enamine, EN300-30498, 954 mg, 3.87 mmol)4-Fluoro-3-Methylaniline (485 mg, 3.87 mmol), COMU (1825 mg, 4.261 mmol)and triethylamine (2.15 mL, 4.26 mmol) in dichloromethane (50 mL) wasstirred for 3 hours. The reaction mixture was washed with 1M HCl (50mL), water and NaHCO₃ solution, dried over sodium sulphate, filtered andconcentrated. The obtained residue was purified by Preparative HPLC(Stationary phase: RP Vydac Denali C18—10 m, 200 g, 5 cm), Mobile phase:0.25% NH₄HCO₃ solution in water, CH₃CN). The product fractions wereconcentrated yielding a white powder which was dried overnight in vacuoat 50° C. (30 mg). Method A; Rt: 1.73 min. m/z: 354.0 (M+H)⁺ Exact mass:353.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.6 Hz, 6H), 2.23 (d,J=1.8 Hz, 3H), 3.21-3.30 (m, 1H), 3.91 (s, 3H), 7.09 (t, J=9.2 Hz, 1H),7.17 (d, J=6.8 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.45-7.57 (m, 2H), 7.64(dd, J=7.0, 2.4 Hz, 1H), 10.01 (s, 1H).

Synthesis of 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride and5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride

1-Methyl-1H-pyrrole-2-carboxylic acid (5520 mg, 44.1 mmol) was dissolvedportion wise in chlorosulfonic acid (25 mL) in an ice bath. The mixturewas stirred for 70 minutes. The mixture was added drop wise to ice/water(200 mL) and stirred for 5 minutes. The precipitate was filtered, rinsedwith water and dried overnight in vacuo at 50° C. resulting in4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylic acid as a powder (5632mg). Oxalyl chloride (22.4 g, 176.8 mmol) was added portion wise to4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylic acid (obtained asdescribed above, 7.9 g, 35.37 mmol) and DMF (0.14 mL) in CH₂Cl₂ (200 mL)and the mixture was stirred over weekend at room temperature. Thereaction mixture was concentrated yielding4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride as a brown solid(8.6 g) which was used as such. 4-fluoro-3-methyl-aniline (2049 mg,16.37 mmol) was dissolved in toluene (20 mL) and added drop wise to asolution of 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (3963mg, 16.37 mmol) in toluene (200 mL) at reflux. The reaction mixture wasrefluxed 1 hour and allowed to cool to room temperature overnight. Theformed precipitate was filtered and dried in vacuo at 50° C. resultingin 5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (3.14 g) as a powder. Method A; Rt: 1.96 min. m/z: 328.9 (M−H)⁻Exact mass: 330.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.29 (d, J=1.8Hz, 3H), 4.05 (s, 3H), 7.00 (t, J=9.0 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H),7.27-7.32 (m, 1H), 7.42 (dd, J=6.6, 2.6 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H),7.63 (br. s., 1H).

Compound 3:N-(4-fluoro-3-methyl-phenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

A mixture of D-alaninol (696 mg, 9.08 mmol) and DIPEA (1.3 mL, 7.57mmol) dissolved in dichloromethane (25 mL) was added to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (2250 mg). The reaction mixture was stirred 15 minutes. MoreD-alaninol (1.5 eq) and DIPEA (2 eq) were added and the reaction mixturewas stirred 15 minutes more. The reaction mixture was washed with 1M HCl(3×), water and NaHCO₃ solution. The organic layer was dried over MgSO₄,filtered and concentrated. The obtained residue was purified by columnchromatography on silica using a gradient from 10 to 100% EtOAc inheptane. The product fractions were concentrated and the obtainedresidue was crystallized from warm EtOAc (50 mL) by slowly addingheptane. Compound 3 was filtered off as white crystals and dried invacuo at 50° C. (342 mg). Method A; Rt: 1.47 min. m/z: 370.2 (M+H)⁺Exact mass: 369.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98 (d, J=6.2 Hz,3H), 2.23 (d, J=1.5 Hz, 3H), 3.07-3.18 (m, 2H), 3.32-3.39 (m, 1H), 3.91(s, 3H), 4.65 (t, J=5.5 Hz, 1H), 7.03-7.15 (m, 2H), 7.30 (d, J=1.8 Hz,1H), 7.47-7.57 (m, 2H), 7.64 (dd, J=7.0, 2.4 Hz, 1H), 10.02 (s, 1H).

Compound 4:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

A mixture of (S)-Tetrahydro-3-furylamine p-toluenesulfonate salt (822mg, 3.17 mmol) and DIPEA (1.09 mL, 6.34 mmol) in dichloromethane (25mL), was added to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (785 mg) in dichloromethane (50 mL) and stirred overnight. Thereaction mixture was washed with 1M HCl (3×), water and NaHCO₃ solution.The organic layer was dried over MgSO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica using a gradientfrom 10 to 100% EtOAc in heptane. The product fractions wereconcentrated yielding compound 4 as a beige solid which was driedovernight in vacuo at 50° C. (696 mg). Method A; Rt: 1.57 min. m/z:382.0 (M+H)⁺ Exact mass: 381.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.77 (m, 1H), 1.91-2.04 (m, 1H), 2.23 (d, J=1.5 Hz, 3H), 3.39-3.47(m, 1H), 3.61 (td, J=8.0, 5.9 Hz, 1H), 3.66-3.76 (m, 3H), 3.92 (s, 3H),7.09 (t, J=9.1 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.47-7.59 (m, 3H), 7.64(dd, J=7.2, 2.3 Hz, 1H), 10.03 (s, 1H).

Compound 5:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

A mixture of 3-methyl-3-oxetanamine hydrochloride (1:1) (391.5 mg, 3.17mmol) and DIPEA (1.09 mL, 6.34 mmol) in dichloromethane (25 mL) wasadded to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (785 mg) in dichloromethane (50 mL) and stirred overnight. Thereaction mixture was washed with 1M HCl (3×), water and NaHCO₃ solution.The organic layer was dried over MgSO₄, filtered and concentrated. Theobtained residue was purified by silica gel column chromatography usinga gradient from 10 to 100% EtOAc in heptane. The product fractions wereconcentrated yielding compound 5 as a beige solid which was driedovernight in vacuo at 50° C. (584 mg). Method A; Rt: 1.57 min. m/z:399.2 (M+NH₄)⁺ Exact mass: 381.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55(s, 3H), 2.23 (d, J=1.5 Hz, 3H), 3.91 (s, 3H), 4.13 (d, J=6.0 Hz, 2H),4.60 (d, J=6.0 Hz, 2H), 7.09 (t, J=9.1 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H),7.48-7.54 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.63 (dd, J=7.0, 2.4 Hz, 1H),7.94 (s, 1H), 10.02 (s, 1H).

Compound 6:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-1-methylpropyl]-sulfamoyl]pyrrole-2-carboxamide

A mixture of (R)-(−)-2-aminobutane (231.7 mg, 3.17 mmol) and DIPEA (1.09mL, 6.34 mmol) in dichloromethane (25 mL) was added to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (785 mg) in dichloromethane (50 mL) and stirred overnight. Thereaction mixture was washed with 1M HCl (3×), water and NaHCO₃ solution.The organic layer was dried over MgSO₄, filtered and concentrated. Theobtained residue was purified by column chromatography on silica using agradient from 10 to 100% EtOAc in heptane. The product fractions wereconcentrated yielding compound 6 as a beige solid which was driedovernight in vacuo at 50° C. (540 mg). Method A; Rt: 1.78 min. m/z:368.1 (M+H)⁺ Exact mass: 367.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77 (t,J=7.4 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H), 1.29-1.41 (m, 2H), 2.23 (d, J=1.5Hz, 3H), 3.01-3.12 (m, 1H), 3.91 (s, 3H), 7.04-7.16 (m, 2H), 7.30 (d,J=2.0 Hz, 1H), 7.46-7.57 (m, 2H), 7.64 (dd, J=7.0, 2.4 Hz, 1H), 10.00(s, 1H).

Alternative Synthesis of Compound 2:

A solution of isopropylamine (499 mg, 8.45 mmol) in dichloromethane (25mL) was added to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (785 mg). The reaction mixture was stirred overnight. Thereaction mixture was washed with 1M HCl (3×), water and NaHCO₃ solution.The organic layer was dried over MgSO₄, filtered and concentrated. Theobtained residue was recrystallized by slowly adding heptanes to warmEtOAc (50 mL) solution of compound 2. Compound 2 was filtered off aswhite solid and dried in vacuo at 50° C. (357 mg).

Compound 7:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)methyl-sulfamoyl]pyrrole-2-carboxamide

A solution of 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride(5.05 g, 0.021 mol) in toluene (225 mL) was stirred at reflux underN₂-flow. A solution of 4-fluoro-3-methyl-aniline (2.56 g, 0.020 mol) intoluene (25 mL) was added dropwise over 35 minutes. After addition, thereaction mixture was stirred and refluxed for 1 hour. The reactionmixture was cooled to ˜50° C. and the solvent was removed in vacuoresulting in crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride. Part of this crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.63 g, 1.9 mmol) and 3-methyloxetan-3-yl)methanamine (212 mg,2.1 mmol) were dissolved in dichloromethane (10 mL). Thendiisopropylethylamine (820 μL, 4.8 mmol) was added and the resultingmixture was stirred for two hours. HCl (5 mL, aq/1M) was added to themixture and the organic layer was separated and loaded directly on asilica plug purified by silica gel column chromatography using gradientelution from heptane to EtOAc (100:0 to 0:100). The desired fractionswere concentrated in vacuo and dried in vacuo resulting in compound 7(586 mg) as a white powder. Method A; Rt: 1.60 min. m/z: 394.0 (M−H)⁻Exact mass: 395.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.24 (s, 3H),2.23 (d, J=1.8 Hz, 3H), 2.96 (s, 2H), 3.92 (s, 3H), 4.17 (d, J=5.8 Hz,2H), 4.34 (d, J=5.8 Hz, 2H), 7.10 (t, J=9.2 Hz, 1H), 7.32 (d, J=1.8 Hz,1H), 7.41-7.54 (m, 2H), 7.57 (d, J=1.8 Hz, 1H), 7.64 (dd, J=6.6, 2.2 Hz,1H), 10.04 (s, 1H).

Compound 8:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (obtained as described in the synthesis of compound 7, 0.5 g,1.51 mmol) and (S)-1,1,1-trifluoro-2-propylamine (0.38 g, 3.33 mmol)were dissolved in of acetonitrile (9 mL). Then diisopropylethylamine(0.78 mL, 4.53 mmol) was added and the resulting mixture was stirred fortwo hours. HCl (5 mL, aq/1M) was added and the mixture was extractedusing dichloromethane (3×25 mL) The combined extracts were dried onsodium sulphate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography using gradient elution fromheptane to EtOAc (100:0 to 0:100). The desired fractions wereconcentrated in vacuo and dried in vacuo resulting in compound 8 (557mg) as a white powder. Method B; Rt: 1.03 min. m/z: 406.1 (M−H)⁻ Exactmass: 407.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H),2.23 (d, J=1.5 Hz, 3H), 3.83-4.01 (m, 4H), 7.10 (t, J=9.1 Hz, 1H), 7.33(d, J=2.0 Hz, 1H), 7.47-7.55 (m, 1H), 7.57-7.69 (m, 2H), 8.15 (br. s.,1H), 9.90-10.13 (br. s., 1H).

Columns: AD-H (250 mm×4.6 mm), Flow: 5 ml/min, Mobile phase: 25% MeOH(containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1 min and hold 2.00min at 50%, Temperature: 40° C. R_(t) (compound 8): 1.2 min.

Compound 9:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (obtained as described in the synthesis of compound 7, 0.69 g,2.09 mmol), (R)-1,1,1-trifluoro-2-propylamine (472 mg, 4.2 mmol) andDIPEA (0.72 mL, 4.2 mmol) where stirred in a sealed tube at 55° C. for16 hours. The reaction mixture was allowed to reach room temperature,and left for 4 hours. The solid was filtered off and washed with CH₃CN(2×). The solvent of the filtrate was evaporated and the obtainedresidue was dissolved in CH₂Cl₂-heptane and then purified by silica gelcolumn chromatography (heptane-EtOAc 100/0 to 0/100]. The desiredfractions were combined and the solvent removed in vacuo. The obtainedresidue was stirred in CH₂Cl₂ (5 mL), filtered and washed with CH₂Cl₂(2×) resulting in compound 9 (0.244 g). Method A; Rt: 1.78 min. m/z:408.1 (M+H)⁺ Exact mass: 407.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d,J=7.0 Hz, 3H), 2.23 (d, J=1.5 Hz, 3H), 3.87-3.96 (m, 4H), 7.10 (dd,J=9.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.47-7.55 (m, 1H), 7.59-7.66 (m,2H), 8.15 (br. s., 1H), 10.03 (s, 1H).

Columns: AD-H (250 mm×4.6 mm), Flow: 5 ml/min, Mobile phase: 25% MeOH(containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1 min and hold 2.00min at 50%, Temperature: 40° C. R_(t) (compound 9): 1.6 min.

Compound 10:N-(4-fluoro-3-methyl-phenyl)-4-[[3-(hydroxymethyl)oxetan-3-yl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

DIPEA (1.44 mL, 0.008 mol) was added to a stirring mixture of crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (obtained as described in the synthesis of compound 7, 1.38 g,0.0042 mol) and CH₂Cl₂ (45 mL). (3-aminooxetan-3-yl)methanol, 0.47 g,0.0046 mol) was added, and the reaction mixture was stirred at roomtemperature for 16 hours. The volatiles were evaporated. The residue wasstirred in EtOAc (50 mL) and washed with HCl 1M (25 mL). The separatedorganic layer was dried with Na₂SO₄, filtered off and evaporated. Theobtained residue was dissolved in EtOAc (3 mL), and heptane (2 mL) wasadded. The resulting solution was left standing overnight. The formedprecipitate was filtered off, washed with a minimum amount EtOAc (3×)and dried in vacuo. The obtained solid was recrystalyzed from CH₃CN (20mL) filtered off, washed with CH₃CN (3×), and dried in vacuo, resultingin compound 10 (767 mg). Method A; Rt: 1.41 min. m/z: 395.9 (M−H)⁻ Exactmass: 397.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (d, J=1.8 Hz, 3H),3.61 (d, J=5.7 Hz, 2H), 3.91 (s, 3H), 4.39 (d, J=6.4 Hz, 2H), 4.56 (d,J=6.4 Hz, 2H), 5.08 (t, J=5.6 Hz, 1H), 7.10 (t, J=9.2 Hz, 1H), 7.33 (d,J=2.0 Hz, 1H), 7.49-7.54 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.64 (dd=7.2,2.3 Hz, 1H), 7.88 (s, 1H), 10.02 (s, 1H).

Compound 11:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyltetrahydrofuran-3-yl)sulfamoyl]pyrrole-2-carboxamide

Crude5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (obtained as described in the synthesis of compound 7, 690 mg)was stirred in CH₂Cl₂ (25 mL), 3-methyloxolan-3-amine hydrochloride (316mg, 2.3 mmol) and DIPEA (0.9 mL, 5.2 mmol) were added and the mixturewas stirred at room temperature for 17 hours. Ethylacetate (300 mL) wasadded and the mixture was washed with 0.5 M HCl (1×100 mL). The organiclayer was dried with Na₂SO₄ and the solvent was evaporated. The obtainedresidue was purified by silica gel column chromatographyMethanol/Dichloromethane 2/98 to 4/96]. The desired fractions werecombined and the solvent was evaporated. The mixture was repurified bysilica gel column chromatography using EtOAc/Heptane 50/50 to 100/0].The desired fractions were combined and the solvent was evaporated. Theobtained residue was recrystallized from 2-Propanol (7 mL). The obtainedwhite solid was filtered off, washed with 2-Propanol (2×2 mL) and driedin vacuo, resulting in compound 11 (211 mg). Method A; Rt: 1.62 min.m/z: 394.1 (M−H)⁻ Exact mass: 395.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.29 (s, 3H), 1.73 (dt, J=12.7, 7.3 Hz, 1H), 2.11-2.28 (m, 4H), 3.39 (d,J=8.6 Hz, 1H), 3.66-3.79 (m, 3H), 3.91 (s, 3H), 7.09 (t, J=9.2 Hz, 1H),7.31 (d, J=1.8 Hz, 1H), 7.46-7.56 (m, 3H), 7.64 (dd, J=7.0, 2.2 Hz, 1H),10.02 (s, 1H).

Compound 12:N-(4-fluoro-3-methyl-phenyl)-4-[[1-(hydroxymethyl)cyclopropyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 12 was prepared similarly as described for compound 11, using1-amino-cyclopropanemethanol instead of 3-methyloxolan-3-aminehydrochloride. After work up, the obtained solid was stirred in boilingCH₂Cl₂ and filtered off. The obtained white solid was recrystallizedfrom Acetonitrile, resulting in compound 12 (1.021 g). Method B; Rt:0.84 min. m/z: 380.1 (M−H)⁻ Exact mass: 381.1. ¹H NMR (360 MHz, DMSO-d₆)δ ppm 0.54-0.65 (m, 4H), 2.23 (d, J=1.8 Hz, 3H), 3.37 (d, J=5.9 Hz, 2H),3.90 (s, 3H), 4.59 (t, J=5.9 Hz, 1H), 7.10 (t, J=9.1 Hz, 1H), 7.27 (d,J=1.8 Hz, 1H), 7.49-7.55 (m, 2H), 7.65 (dd, J=7.1, 2.4 Hz, 1H), 7.75 (s,1H), 10.03 (s, 1H).

Compound 13:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[(1-methyl-5-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrole-2-carboxamide

Compound 13 was prepared similarly as described for compound 7, using4-amino-1-methyl-pyrrolidin-2-one hydrochloride instead of3-methyloxetan-3-yl)methanamine. Method B; Rt: 0.81 min. m/z: 409.1(M+H)⁺ Exact mass: 408.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07-2.15 (m,1H), 2.23 (d, J=1.8 Hz, 3H), 2.35-2.50 (m, 1H), 2.67 (s, 3H), 3.18 (dd,J=10.1, 4.6 Hz, 1H), 3.52 (dd, J=10.1, 7.3 Hz, 1H), 3.76-3.85 (m, 1H),3.92 (s, 3H), 7.10 (t, J=9.2 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.46-7.55(m, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.64 (dd, J=7.0, 2.6 Hz, 1H), 7.72 (br.s, 1H), 10.03 (s, 1H). Compound 13, was separated in it's enantiomerscompound 13a and compound 13b by preoperative SFC (Stationary phase:Chiralpak Daicel IC 20×250 mm), Mobile phase: CO₂, MeOH with 0.4%iPrNH₂) The desired fractions were concentrated in vacuo and dried invacuo yielding compound 13a (192 mg) and compound 13b (200 mg) as whitepowders. Columns: ID-H (diacel) 250 mm×4.6 mm, Flow: 5 mL/min. Mobilephase: 30% MeOH (containing 0.2% iPrNH₂) hold 4.00 min, up to 50% in 1min and hold 2.00 min at 50%. Temperature: 40° C. Rt: 13a: 2.2 min; 13b2.5 min.

Compound 14:N-(4-fluoro-3-methyl-phenyl)-4-[[3-(2-hydroxyethyl)oxetan-3-yl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 14 was prepared similarly as described for compound 7, using2-(3-aminooxetan-3-yl)ethanol instead of3-methyloxetan-3-yl)methanamine, resulting in compound 14 (1.09 g) as awhite powder. Method B; Rt: 0.80 min. m/z: 410.1 (M−H)⁻ Exact mass:411.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.14 (t, J=6.6 Hz, 2H), 2.23 (d,J=1.5 Hz, 3H), 3.42-3.50 (m, 2H), 3.91 (s, 3H), 4.32 (d, J=6.4 Hz, 2H),4.45 (br. s, 1H), 4.56 (d, J=6.4 Hz, 2H), 7.10 (t, J=9.1 Hz, 1H), 7.33(d, J=1.8 Hz, 1H), 7.46-7.54 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.63 (dd,J=7.0, 2.4 Hz, 1H), 7.84 (br. s., 1H), 10.02 (s, 1H).

Compound 15:N-(4-fluoro-3-methyl-phenyl)-4-[(3-hydroxycyclobutyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide

5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.56 g, 1.7 mmol) was stirred in CH₂Cl₂ (15 mL).cis-3-aminocyclobutanol hydrochloride (0.23 g, 1.9 mmol) and DIPEA (1.5mL, 8.5 mmol) were added at room temperature and the mixture was stirredfor 60 hour. The solvent was evaporated and the obtained residue waspurified by silica gel column chromatography (Methanol/Dichloromethane2/98 to 4/96). The pure fractions were combined and the solvent wasevaporated and the obtained residue was crystallized fromdichloromethane, resulting in compound 15 (273 mg) as a white solidafter filtration and drying in vacuo. Method B; Rt: 0.81 min. m/z: 380.1(M−H)⁻ Exact mass: 381.1 ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.59-1.71 (m,2H), 2.22 (d, J=1.5 Hz, 3H), 2.28-2.38 (m, 2H), 3.02-3.16 (m, 1H),3.63-3.75 (m, 1H), 3.90 (s, 3H), 5.02 (d, J=5.9 Hz, 1H), 7.10 (dd, J=9.1Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.47-7.55 (m, 3H), 7.65 (dd, J=7.1, 2.4Hz, 1H), 10.03 (s, 1H).

Compound 16:4-(tert-butylsulfamoyl)-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.60 g, 1.8 mmol) was stirred in CH₂Cl₂ (15 mL).tert-butylamine (0.23 g, 1.9 mmol) and DIPEA (0.8 mL, 4.5 mmol) wereadded at room temperature and the mixture was stirred for 18 hours. Thesolvent was evaporated and EtOAc (50 mL) was added. After washing with1M HCl (20 mL), the organic layer was dried with Na₂SO₄ and the solventwas evaporated. The obtained solid was dissolved in dichloromethane (10mL) and the solvent was slowly evaporated at 50° C. The evaporation wasstopped when precipitation commenced, and stirring was continued at roomtemperature for 15 minutes. The precipitate was filtered off, washedwith dichloromethane (1 mL) and dried in vacuo at 50° C., resulting incompound 16 (136 mg). Method A; Rt: 1.79 min. m/z: 366.1 (M−H)⁻ Exactmass: 367.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 2.23 (d,J=1.5 Hz, 3H), 3.90 (s, 3H), 7.05-7.13 (m, 2H), 7.29 (d, J=1.8 Hz, 1H),7.45-7.55 (m, 2H), 7.64 (dd, J=7.0, 2.2 Hz, 1H), 10.00 (s, 1H).

Compound 17:4-[[3-(cyanomethyl)oxetan-3-yl]sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

Compound 10 (0.46 g, 1.2 mmol) was dissolved in dry dichloromethane (30mL) and dry DIPEA (0.31 mL, 1.8 mmol) was added. This mixture was cooledin an ice bath and stirred for 20 minutes. Then Methanesulfonyl Chloride(0.10 mL, 1.3 mmol) in dry dichloromethane (10 mL) was added dropwiseover 10 minutes, after stirring 30 minutes more at 0° C., the mixturewas washed with 0.5 M HCl (50 mL) and saturated aqueous NaHCO₃ (5 mL).The water layer was extracted with EtOAc (200 mL) and the combinedorganic layers were dried with Na₂SO₄. The solvent was removed in vacuoand the obtained residue was dissolved in dry DMSO. This solution wasadded dropwise to a solution of sodium cyanide (0.12 g, 2.4 mmol) in dryDMSO (25 mL) at 40° C. The mixture was stirred 2.5 hour at 40° C. Aftercooling to room temperature water (50 mL) was added. This mixture wasextracted with diethylether (3×100 mL) and EtOAc (3×150 mL). Thecombined organic layer were dried on Na₂SO₄ and the solvent wasevaporated. The obtained residue was purified by silica gel columnchromatography by gradient elution with EtOAc/Heptane 0/100 to 100/0].The desired fractions were combined and the solvent was removed,resulting compound 17 (264 mg) as a beige solid after drying in vacuo.Method B; Rt: 0.86 min. m/z: 405.2 (M−H)⁻ Exact mass: 406.1 ¹H NMR (360MHz, DMSO-d₆) δ ppm 2.23 (d, J=1.8 Hz, 3H), 3.28 (s, 2H), 3.91 (s, 3H),4.28 (d, J=7.0 Hz, 2H), 4.55 (d, J=7.0 Hz, 2H), 7.11 (t, J=9.3 Hz, 1H),7.35 (d, J=2.2 Hz, 1H), 7.47-7.55 (m, 1H), 7.61-7.67 (m, 2H), 8.46-8.53(m, 1H), 10.05 (s, 1H).

Compound 18:4-[[1-(cyanomethyl)cyclopropyl]sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

Prepared similarly as described for compound 17, starting from compound12 instead of compound 10. Method C; Rt: 1.69 min. m/z: 389.1 (M−H)⁻Exact mass: 390.1.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 0.63-0.74 (m, 4H), 2.23 (d, J=1.8Hz, 3H), 2.81 (s, 2H), 3.92 (s, 3H), 7.07-7.15 (m, 1H), 7.26-7.31 (m,1H), 7.49-7.59 (m, 2H), 7.62-7.68 (m, 1H), 8.13-8.20 (m, 1H),10.02-10.09 (m, 1H).

Compound 19:4-(tert-butylsulfamoyl)-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide

A solution of 3,4-difluoroaniline (1.9 mL, 19.2 mmol) in toluene (20 mL)was added dropwise (over 15 minutes) to a refluxing solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride in toluene (250mL). After the addition, the reaction mixture was left to stir at refluxfor 1 hour. The reaction mixture was left to cool to room temperatureunder nitrogen atmosphere while stirring. The grey suspension wasconcentrated and the obtained residue containing5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloridewas dried in vacuo and further used without further purification.Tert-butylamine (0.3 mL, 2.8 mmol) was added to a suspension of crude5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride(1.2 g, 2.55 mmol) in dry dichloromethane (20 mL) at room temperature.Next, NEt₃ (0.9 mL, 6.4 mmol) was added dropwise and the reactionmixture was stirred at room temperature for 1 hour and at 50° C. for 1.5hour. The reaction mixture was diluted with EtOAc (250 mL). 0.5 N HCl(30 mL) was added to the reaction mixture and the layers were separated.The organic layer was washed again with 0.5 N NaOH (30 mL), followed bywater. The organic layer was dried on MgSO₄, filtered and evaporated.The obtained residue was purified by silica gel column chromatography(eluent: CH₂Cl₂:MeOH 100:0->95:5). The obtained white solid wastriturated in a small amount of CH₂Cl₂. After filtration, washing withCH₂Cl₂ and drying in vacuo, compound 19 (310 mg) was obtained as a whitesolid. Method B; Rt: 1.02 min. m/z: 370.1 (M−H)⁻ Exact mass: 371.1. ¹HNMR (360 MHz, DMSO-d₆) δ ppm 1.16 (s, 9H) 3.90 (s, 3H) 7.16 (s, 1H) 7.31(d, J=1.8 Hz, 1H) 7.35-7.46 (m, 1H) 7.45-7.53 (m, 1H) 7.54 (d, J=1.5 Hz,1H) 7.88 (ddd, J=13.5, 7.8, 2.2 Hz, 1H) 10.24 (s, 1H).

Compound 20:N-(3,4-difluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

Compound 20 was prepared similarly as described for compound 19, using3-methyl-3-oxetanamine hydrochloride instead of tert-butylamine. Afterwork-up the obtained residue was triturated in a small amount of CH₂Cl₂and filtered resulting in a white powder. The powder was triturated inEtOAc (1 mL), filtered and rinsed with a small amount of CH₂Cl₂resulting in compound 20 (421 mg) as a white powder after drying invacuo. Method B; Rt: 0.86 min. m/z: 384.1 (M−H)⁻ Exact mass: 385.1. ¹HNMR (360 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H) 3.91 (s, 3H) 4.13 (d, J=6.2Hz, 2H) 4.59 (d, J=6.2 Hz, 2H) 7.33 (d, J=1.8 Hz, 1H) 7.37-7.46 (m, 1H)7.46-7.52 (m, 1H) 7.61 (d, J=1.8 Hz, 1H) 7.87 (ddd, J=13.5, 7.4, 2.6 Hz,1H) 8.00 (s, 1H) 10.25 (s, 1H).

Compound 21:N-(3,4-difluorophenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

A solution of 3,4-difluoroaniline in toluene (50 mL) was slowly added(over 1 hour) to a refluxing solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride in toluene (200mL). After addition, the reaction mixture was left to stir at reflux for45 minutes.

The reaction mixture was left to cool to room temperature under nitrogenatmosphere while stirring and was then cooled with an ice bath. Theprecipitate was filtered and the filtrate was concentrated and dried invacuo, resulting in a residue containing5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride.(S)-3-aminotetrahydrofuran tosylate (0.59 g, 2.3 mmol) was added to asuspension of5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride(1.0 g of the above obtained crude) in dry dichloromethane (50 mL) atroom temperature. NEt₃ (0.72 mL, 5.2 mmol) was added dropwise and themixture was further stirred at room temperature for 1 hour. 0.5 N HCl(30 mL) was added to the reaction mixture and the layers were separated.The organic layer was washed again with 0.5 N NaOH (30 mL) followed bywater. The organic layer was dried on MgSO₄ and was evaporated.

The obtained residue was triturated in a small amount of CH₂Cl₂,filtered, and washed with a small amount of CH₂Cl₂, resulting incompound 21 (408 mg) as a white solid, after drying in vacuo. Method B;Rt: 0.84 min m/z: 384.0 (M−H)⁻ Exact mass: 385.1. ¹H NMR (360 MHz,DMSO-d₆) δ ppm 1.66-1.76 (m, 1H) 1.91-2.03 (m, 1H) 3.40-3.47 (m, 1H)3.61 (td, J=8.1, 5.9 Hz, 1H) 3.65-3.75 (m, 3H) 3.92 (s, 3H) 7.33 (d,J=1.83 Hz, 1H) 7.37-7.46 (m, 1H) 7.46-7.52 (m, 1H) 7.57-7.62 (m, 2H)7.88 (ddd, J=13.5, 7.6, 2.4 Hz, 1H) 10.26 (s, 1H).

Compound 22:N-(3,4-difluorophenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

Compound 22 was prepared similarly as described for compound 21, usingisopropylamine instead of (S)-3-aminotetrahydrofuran tosylate. Afterwork-up (only 0.5 N HCl was used for washing) the obtained residue waspurified by silica gel column chromatography (CH₂Cl₂:MeOH 100:0->95:5)resulting in compound 22 (534 mg) as a white solid after drying invacuo. Method B; Rt: 0.94 min. m/z: 356.1 (M−H)⁻ Exact mass: 357.1. ¹HNMR (360 MHz, DMSO-d₆) δ ppm 1.01 (d, J=6.2 Hz, 6H) 3.18-3.28 (m, 1H)3.91 (s, 3H) 7.23 (d, J=7.0 Hz, 1H) 7.32 (d, J=1.8 Hz, 1H) 7.36-7.46 (m,1H) 7.46-7.53 (m, 1H) 7.56 (d, J=1.8 Hz, 1H) 7.88 (ddd, J=13.4, 7.5, 2.6Hz, 1H) 10.25 (s, 1H).

Compound 23:N-(3,4-difluorophenyl)-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxamide

Compound 23 was prepared similarly as described for compound 22, using(R)-(−)-2-aminobutane instead of isopropylamine. After work up, theobtained residue was triturated in a small amount of CH₂Cl₂, filteredand washed with a small amount of CH₂Cl₂. The obtained solid wastriturated with 0.5 N NaOH and filtered. The white solid was washed withwater resulting in compound 23 (499 mg) as a white solid, after dryingin vacuo. Method B; Rt: 1.00 min. m/z: 370.1 (M−H)⁻ Exact mass: 371.1.¹H NMR (360 MHz, DMSO-d₆) δ ppm 0.76 (t, J=7.5 Hz, 3H) 0.95 (d, J=6.6Hz, 3H) 1.28-1.41 (m, 2H) 3.00-3.13 (m, 1H) 3.91 (s, 3H) 7.18 (d, J=7.7Hz, 1H) 7.32 (d, J=1.8 Hz, 1H) 7.36-7.46 (m, 1H) 7.46-7.53 (m, 1H) 7.56(d, J=1.8 Hz, 1H) 7.88 (ddd, J=13.4, 7.7, 2.4 Hz, 1H) 10.25 (s, 1H).

Compound 24:N-(3,4-difluorophenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 24 was prepared similarly as described for compound 19, usingD-alaninol instead of tert-butylamine, using 5 equiv of NEt₃ and 1.5hour stirring at room temperature. The reaction mixture was diluted withEtOAc (250 mL), 0.5 N HCl (30 mL) was added to the reaction mixture andthe layers were separated. The organic layer was washed again with 0.5 NNaOH (30 mL) followed by water. The organic layer was dried on MgSO₄,filtered and evaporated. The obtained residue was triturated in a smallamount of CH₂Cl₂, filtered and washed with a small amount of CH₂Cl₂resulting in compound 24 (717 mg) as a white powder, after drying invacuo. Method B; Rt: 0.81 min. m/z: 372.0 (M−H)⁻ Exact mass: 373.1 ¹HNMR (360 MHz, DMSO-d₆) δ ppm 0.97 (d, J=5.9 Hz, 3H) 3.06-3.17 (m, 2H)3.32-3.39 (m, 1H), 3.91 (s, 3H) 4.69 (t, J=5.3 Hz, 1H) 7.14 (d, J=6.6Hz, 1H) 7.32 (d, J=1.5 Hz, 1H) 7.36-7.46 (m, 1H) 7.46-7.53 (m, 1H) 7.57(d, J=1.5 Hz, 1H) 7.88 (ddd, J=13.5, 7.6, 2.4 Hz, 1H) 10.25 (s, 1H).

Compound 25:N-(3,4-difluorophenyl)-4-[(3-hydroxycyclobutyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 25 was prepared similarly as described for compound 19, usingcis-3-aminocyclobutanol hydrochloride instead of tert-butylamine andadding 2.5 equiv more NEt₃ before heating to 50° C.

The residue obtained after work up was triturated in a small amount ofCH₂Cl₂, filtered and washed with a small amount of CH₂Cl₂ resulting in awhite powder, which was further triturated in MeOH/CH₂Cl₂ 5/95. Afterfiltration, washing and drying in vacuo, compound 25 (150 mg) wasobtained as a white powder. Method A; Rt: 0.80 min. m/z: 384.0 (M−H)⁻Exact mass: 385.1. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.59-1.71 (m, 2H)2.27-2.39 (m, 2H) 3.03-3.15 (m, 1H) 3.64-3.76 (m, 1H) 3.91 (s, 3H) 5.02(d, J=5.5 Hz, 1H) 7.28-7.33 (m, 1H) 7.36-7.46 (m, 1H) 7.46-7.57 (m, 2H)7.88 (ddd, J=13.5, 7.6, 2.0 Hz, 1H) 10.24 (s, 1H).

Compound 91:N-(3,4-Difluorophenyl)-1-methyl-4-[(3-methyltetrahydrofuran-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 91 was prepared similarly as described for compound 19 using3-methyloxolan-3-amine hydrochloride instead of tert-butylamine.Compound 91 (206 mg) was obtained as a white solid. Method B; Rt: 0.91min. m/z: 398.1 (M−H)⁻ Exact mass: 399.1. ¹H NMR (360 MHz, DMSO-d₆) ppm1.28 (s, 3H) 1.72 (dt, J=12.5, 7.5 Hz, 1H) 2.12-2.21 (m, 1H) 3.38 (d,J=8.8 Hz, 1H) 3.69-3.75 (m, 3H) 3.91 (s, 3H) 7.33 (d, J=2.2 Hz, 1H)7.36-7.46 (m, 1H) 7.46-7.52 (m, 1H) 7.55-7.59 (m, 2H) 7.88 (ddd, J=13.4,7.6, 2.4 Hz, 1H) 10.25 (s, 1H).

Compound 92:N-(3,4-Difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]-sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 92 was prepared similarly as described for compound 19 using(R)-1,1,1-trifluoro-2-propylamine instead of tert-butylamine. Compound92 precipitated from the basic 0.5 N NaOH water layer uponneutralization. Compound 92 was further purified by Preparative HPLC(Stationary phase: Uptisphere C₁₈ ODB—10 m, 200 g, 5 cm), Mobile phase:0.5% NH₄OAc solution in water+10% CH₃CN, CH₃CN). The collected fractionswere concentrated (to the aqueous phase). The aqueous phase wasacidified with HCl 1N and was extracted with EtOAc. The organic layerwas dried on MgSO₄, filtered, and evaporated resulting in compound 92(49 mg) as a white solid after drying in vacuo at 50° C. Method B; Rt:1.03 min. m/z: 410.1 (M−H)⁻ Exact mass: 411.1.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.06 (d, J=7.0 Hz, 3H) 3.92 (s, 3H)3.87-4.00 (m, 1H) 7.35 (d, J=1.8 Hz, 1H) 7.37-7.52 (m, 2H) 7.66 (d,J=1.8 Hz, 1H) 7.88 (ddd, J=13.4, 7.6, 2.4 Hz, 1H) 8.18 (d, J=8.8 Hz, 1H)10.27 (s, 1H).

Compound 93:N-(3,4-Difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 93 was prepared similarly as described for compound 92 using(S)-1,1,1-trifluoro-2-propylamine instead of(R)-1,1,1-trifluoro-2-propylamine. Method B; Rt: 1.03 min. m/z: 410.1(M−H)⁻ Exact mass: 411.1.

Alternative Synthesis of Compound 92:

Methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(6.61 g, 21.0 mmol) and 3,4-difluoroaniline (3.26 g, 25.24 mmol) weredissolved in tetrahydrofuran (150 mL) and this was stirred and cooled inan ice-water bath. Lithium bis(trimethylsilyl)amide in toluene (63.1 mL,1 M, 63.1 mmol) was added dropwise over a period of 5 minutes. Theresulting mixture was stirred for 1 h while cooling was continued.Another two equivalents of lithium bis(trimethylsilyl)amide in toluene(42.06 mL, 1 M, 42.06 mmol) were added and the resulting mixture wasstirred for 2 hours at room temperature. The resulting mixture wasquenched using ammonium chloride (sat./200 mL). The resulting mixturewas extracted using EtOAc (3×250 mL). The combined extracts were washedwith brine (250 mL), dried on Na₂SO₄, filtered and concentrated in vacuoyielding a brown powder. This was crystallised twice out ofmethanol/water. The precipitation was collected on a glass filter. Theobtained powder was purified by silica gel column chromatography usinggradient elution from heptane to EtOAc. (100:0 to 0:100) and next bysilica gel column chromatography using gradient elution fromdichloromethane to MeOH (100:0 to 99:1). The desired fractions wereconcentrated in vacuo yielding a powder. The obtained residue wascrystallized out of methanol/water. The white crystals were collected ona glass filter and dried in a vacuum oven at 55° C. for 24 hoursyielding compound 92 (4.32 g) as white needles. [α]₃₆₅ ²⁰=−11.6° (c 0.85w/v %, MeOH). Differential scanning calorimetry: From 30 to 300° C. at10° C./min: peak at 219.6° C.

Compound 95:N-(3,4-Difluorophenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)-sulfamoyl]-1H-pyrrole-2-carboxamide

5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride(648 mg, 1.374 mmol), 2,2,2-trifluoro-1,1-dimethyl-ethylamine (262 mg),DIPEA (0.296 mL, 1.72 mmol) in acetonitrile (65 mL) was refluxedovernight. 2,2,2-trifluoro-1,1-dimethyl-ethylamine (349 mg) were addedand the reaction mixture was refluxed over weekend. The reaction mixturewas concentrated. The residue was dissolved in EtOAc (100 mL), washedwith 1M HCl, dried over sodium sulphate, filtered and concentrated. Theobtained residue was subjected to silica gel column chromatography usinga gradient from 10 to 100% EtOAc in heptane. The pure fractions werecollected, concentrated and dried in vacuo at 50° C. yielding compound95 as a white powder (162 mg). Method A; Rt: 1.78 min. m/z: 424.1 (M−H)⁻Exact mass: 425.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 6H), 3.92(s, 3H), 7.32 (d, J=1.8 Hz, 1H), 7.36-7.45 (m, 1H), 7.46-7.52 (m, 1H),7.58 (d, J=1.8 Hz, 1H), 7.87 (ddd, J=13.4, 7.6, 2.5 Hz, 1H), 8.04 (s,1H), 10.25 (s, 1H).

Compound 26:1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]-N-(3,4,5-trifluoro-phenyl)pyrrole-2-carboxamide

A solution of 3,4,5-trifluoroaniline (0.99 g, 6.7 mmol) in toluene (20mL) was added dropwise to a refluxing solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride in toluene (80 mL).After the addition, the reaction mixture was left to stir at reflux for1 hour. The mixture was cooled and concentrated in vacuo. The obtainedcrude containing1-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]pyrrole-3-sulfonyl chloridewas used a such. A solution of (S)-(−)-3-aminotetrahydrofuranp-toluenesulfonate (647 mg, 2.5 mmol) and DIPEA (0.98 mL, 5.7 mmol) inCH₂Cl₂ (10 mL) was added to crude1-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]pyrrole-3-sulfonyl chloride(800 mg) in CH₂Cl₂ (150 mL) and stirred for 1 hour. The mixture wasdiluted with dichloromethane (400 mL) and washed with 1M HCl (2×), waterand saturated NaHCO₃ solution. The organic layer was dried overmagnesium sulphate, filtered and concentrated. The obtained residue wasdissolved in hot MeOH (100 mL) and water was added. The formed whiteprecipitate was filtered off, dried in vacuo and purified by silica gelcolumn chromatography using a gradient from 20 to 100% EtOAc in heptane.The product fractions were concentrated and dried in vacuo resulting incompound 26 (286 mg) as a white powder. Method A; Rt: 1.67 min. m/z:401.9 (M−H)⁻ Exact mass: 403.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.66-1.76 (m, 1H), 1.91-2.03 (m, 1H), 3.39-3.47 (m, 1H), 3.55-3.65 (m,1H), 3.65-3.75 (m, 3H), 3.92 (s, 3H), 7.33 (d, J=2.0 Hz, 1H), 7.58 (d,J=5.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.63-7.71 (m, 2H), 10.33 (s, 1H).

Compound 27:1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide

3-methyl-3-oxetanamine hydrochloride (526 mg, 4.3 mmol) and DIPEA (1.8mL) were dissolved in CH₂Cl₂ (5 mL). Crude1-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]pyrrole-3-sulfonyl chloride(1.2 g, obtained as described for compound 26) was added and thereaction mixture was stirred for 30 minutes. The reaction mixture wasdirectly loaded on silica gel column and purified by gradient elutionfrom heptane to EtOAc, yielding compound 27 (758 mg) as a white powderafter trituration in CH₂Cl₂ and drying in vacuo. Method A; Rt: 1.68 min.m/z: 401.9 (M−H)⁻ Exact mass: 403.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.54 (s, 3H), 3.92 (s, 3H), 4.14 (d, J=6.5 Hz, 2H), 4.60 (d, J=6.1 Hz,2H), 7.34 (d, J=1.6 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.66 (dd, J=10.3,6.7 Hz, 2H), 7.98 (s, 1H), 10.32 (s, 1H).

DSC: From 30 to 300° C. at 10° C./min, Peak: 218° C.

Compound28:1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-[3-(trifluoromethyl)-phenyl]pyrrole-2-carboxamide

3-(trifluoromethyl)aniline (0.41 mL, 3.3 mmol) was added dropwise to arefluxing solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride in toluene (25 mL).After the addition, the reaction mixture was left to stir at reflux for4 hours. The mixture was cooled to room temperature and a solution of3-methyl-3-oxetanamine hydrochloride (408 mg, 3.3 mmol) and DIPEA (0.57mL) in CH₂Cl₂ (2 mL) was added. The mixture was stirred overnight atroom temperature. More 3-methyl-3-oxetanamine hydrochloride (0.5 equiv)and DIPEA (0.5 equiv) in CH₂Cl₂ (2 mL) were added and the mixture wasstirred for 2 hours at room temperature and 2 hours more at 50° C. Thereaction mixture was allowed to reach room temperature and the formedprecipitate was filtered off, triturated in MeOH (12 mL), filtered anddried in vacuo, resulting in compound 28 as a white powder. Method B;Rt: 0.99 min. m/z: 416.1 (M−H)⁻ Exact mass: 417.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.55 (s, 3H), 3.93 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.60(d, J=5.9 Hz, 2H), 7.39 (d, J=2.0 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.58(t, J=8.0 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.95-8.02 (m, 2H), 8.19 (s,1H), 10.32 (s, 1H).

Compound 29:1-ethyl-N-(4-fluoro-3-methyl-phenyl)-4-(isopropylsulfamoyl)pyrrole-2-carboxamide

To 4-chlorosulfonyl-1-ethyl-pyrrole-2-carboxylic acid (1 g, commercialfrom enamine, EN300-43738, 4.2 mmol) in CH₂Cl₂, (10 mL) at roomtemperature under N₂-atmosphere, DMF (1 drop) was added followed bydropwise addition of a solution of oxalyl chloride (1.44 mL, 0.0168 mol)in CH₂Cl₂ (5 mL) over 10 minutes. After addition, the reaction mixtureas stirred at room temperature for 24 hours. The volatiles wereevaporated, and co-evaporated with dry toluene (2×). The obtainedresidue containing 4-chlorosulfonyl-1-ethyl-pyrrole-2-carbonyl chloridewas used as such in the next step.

A solution of 4-fluoro-3-methylaniline (527 mg, 4.2 mmol) in toluene wasadded dropwise to a solution of the above obtained crude4-chlorosulfonyl-1-ethyl-pyrrole-2-carbonyl chloride in toluene atreflux over 5 minutes. The reaction mixture was refluxed 30 minutes andnext allowed to reach room temperature. After stirring at roomtemperature for 2 hours the volatiles were removed in vacuo resulting ina residue containing1-ethyl-5-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrole-3-sulfonylchloride that was used as such in the next step. Part of the as suchobtained crude1-ethyl-5-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrole-3-sulfonylchloride (708 mg) was dissolved in CH₂Cl₂ (5 mL) and isopropylamine(0.13 mL, 1.6 mmol) and DIPEA (0.72 mL, 4.2 mmol) were added and thereaction mixture stirred at room temperature for 30 minutes. The mixturewas diluted with EtOAc (100 mL) and washed with 1 M HCl (2×10 mL). Theorganic layer was dried on Na₂SO₄, filtered and concentrated resultingin a residue that was purified using silica gel column chromatography(ethyl acetate in heptane from 10 to 100%) resulting in compound 29 (270mg). Method B; Rt: 1.02 min. m/z: 366.2 (M−H)⁻ Exact mass: 367.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.01 (d, J=6.6 Hz, 6H), 1.31 (t, J=7.0 Hz, 3H),2.23 (d, J=1.5 Hz, 3H), 3.20-3.33 (m, 1H), 4.38 (q, J=7.0 Hz, 2H), 7.09(t, J=9.1 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H),7.48-7.54 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.64 (dd, J=7.0, 2.4 Hz, 1H),10.03 (br. s, 1H).

Compound 30:1-ethyl-N-(4-fluoro-3-methyl-phenyl)-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

Crude 1-ethyl-5-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrole-3-sulfonylchloride (obtained as described for compound 29) was dissolved in CH₂Cl₂(5 mL) and (S)-(−)-3-aminotetrahydrofuran p-toluenesulfonate (410 mg,1.6 mmol)) and DIPEA (0.7 mL, 4.2 mmol) were added and the reactionmixture stirred at room temperature for 30 minutes. The mixture wasdiluted with EtOAc (100 mL) and washed with 1M HCl (2×10 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo toafford a residue that was purified using silica gel columnchromatography (ethyl acetate in heptane from 10 to 100%) resulting incompound 30 (282 mg) as white powder after drying in vacuo. Method B;Rt: 0.92 min. m/z: 394.1 (M−H)⁻ Exact mass: 395.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.32 (t, J=7.0 Hz, 3H), 1.64-1.75 (m, 1H), 1.90-2.02 (m,1H), 2.23 (d, J=1.5 Hz, 3H), 3.36-3.45 (m, 1H), 3.61 (td, J=8.0, 5.9 Hz,1H), 3.66-3.78 (m, 3H), 4.39 (q, J=7.1 Hz, 2H), 7.09 (t, J=9.1 Hz, 1H),7.30 (d, J=1.8 Hz, 1H), 7.46-7.56 (m, 2H), 7.61 (d, J=1.8 Hz, 1H), 7.64(dd, J=7.0, 2.4 Hz, 1H), 10.04 (br. s, 1H).

Compound 31:N-(4-fluoro-3,5-dimethyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

4-fluoro-3,5-dimethyl-benzenamine (995 mg, 7.1 mmol) dissolved intoluene (20 mL) was added dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (1.7 g) in toluene(100 mL) at reflux. The reaction mixture was refluxed 1 hour and nextallowed to cool to room temperature. (S)-(−)-3-aminotetrahydrofuranp-toluenesulfonate (2.0 g, 7.9 mmol) and DIPEA (3.1 mL, 17.9 mmol)dissolved in CH₂Cl₂ (50 mL) was added, the reaction mixture was stirredfor 1 hour and then concentrated in vacuo. The obtained residue wasdissolved in EtOAc (300 mL), washed with 1 M HCl (2×), water andsaturated NaHCO₃. The solution was dried over magnesium sulphate,filtered and concentrated. The obtained residue was purified by silicagel column chromatography (gradient from 20 till 100% EtOAc inheptanes). The product fractions were concentrated and the obtainedresidue was recrystallized from hot EtOAc (100 mL) upon addition ofheptane. The white crystals were filtered off and dried in vacuoresulting in compound 31 (1.7 g) as a white powder. Method A; Rt: 1.68min. m/z: 393.9 (M−H)⁻ Exact mass: 395.1. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.66-1.77 (m, 1H), 1.92-2.03 (m, 1H), 2.21 (d, J=2.0 Hz, 6H),3.40-3.47 (m, 1H), 3.61 (td, J=8.1, 5.9 Hz, 1H), 3.66-3.76 (m, 3H), 3.91(s, 3H), 7.31 (d, J=2.0 Hz, 1H), 7.43 (d, J=6.8 Hz, 2H), 7.50-7.58 (m,2H), 9.94 (s, 1H).

Compound 32:N-(3-fluoro-5-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

Compound 32 was prepared similarly as described for compound 31, using3-fluoro-5-methylaniline instead of 4-fluoro-3,5-dimethyl-benzenamine.After silica gel column chromatography (EtOAc in heptanes 20% to 100%),compound 32 (2.2 g) was obtained as a white powder. Method A; Rt: 1.62min. m/z: 379.9 (M−H)⁻ Exact mass: 381.1. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.66-1.77 (m, 1H), 1.92-2.03 (m, 1H), 2.30 (s, 3H), 3.40-3.47 (m,1H), 3.61 (td, J=8.0, 5.9 Hz, 1H), 3.66-3.76 (m, 3H), 3.92 (s, 3H), 6.75(d, J=9.7 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.35-7.38 (m, 1H), 7.47 (d,J=11.7 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 10.12(s, 1H).

Compound 33:N-(3,4-difluoro-5-methyl-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

3,4-difluoro-5-methylbenzoic acid (Alfa Aesar, H32313-03, 4.8 g, 26.9mmol) was dissolved in t-BuOH (100 mL). NEt₃ (4.1 mL, 29.6 mmol) wasadded followed by diphenylphosphoryl azide (7.5 g, 27.4 mmol) and thereaction mixture was refluxed overnight. The mixture was concentratedand the obtained residue was purified by silica gel columnchromatography using a gradient from 30 till 100% EtOAc in heptane. Theproduct fractions were concentrated in vacuo yielding tert-butylN-(3,4-difluoro-5-methyl-phenyl)carbamate (4.15 g) as a white powder. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 9H), 2.22 (d, J=1.8 Hz, 3H), 7.11(d, J=5.1 Hz, 1H), 7.26-7.38 (m, 1H), 9.47 (br. s., 1H). To a tert-butylN-(3,4-difluoro-5-methyl-phenyl)carbamate (4.15 g) in CH₂Cl₂ (100 mL),HCl (6M in iPrOH, 13.7 mL) was added and the mixture was stirred for 3hours. The reaction mixture was concentrated in vacuo. The white solidresidue was dissolved in water (100 mL), alkalinized with 1M NaOH andextracted with ether. The organic layer was dried over MgSO₄, filteredand concentrated yielding 3,4-difluoro-5-methyl-aniline as a colorlessoil which was stored under nitrogen in the dark and used a such. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.13 (d, J=2.2 Hz, 3H), 5.11 (s, 2H), 6.16-6.23(m, 1H), 6.31 (ddd, J=12.9, 6.5, 2.8 Hz, 1H).3,4-difluoro-5-methyl-aniline (209 mg, 1.5 mmol) dissolved in toluene(20 mL) was added dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (353 mg) in toluene(30 mL) at reflux. The reaction mixture was refluxed 2 hours, allowed tocool to room temperature and concentrated in vacuo. Isopropylamine (216mg, 3.7 mmol) dissolved in CH₂Cl₂ (50 mL) was added and the reactionmixture was stirred overnight and next concentrated in vacuo. Theobtained residue was dissolved in hot methanol (100 mL) and H₂O wasadded. The formed precipitate was filtered off and dried in vacuo,resulting in compound 33 (385 mg). Method A; Rt: 1.83 min. m/z: 370.0(M−H)⁻ Exact mass: 371.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.4Hz, 6H), 2.28 (d, J=2.0 Hz, 3H), 3.21-3.30 (m, 1H), 3.91 (s, 3H), 7.19(d, J=7.0 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.41 (d, J=5.9 Hz, 1H), 7.54(d, J=1.8 Hz, 1H), 7.66 (ddd, J=12.9, 7.1, 2.4 Hz, 1H), 10.13 (s, 1H).

Compound 34:N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[[(1R)-1-methylpropyl]-sulfamoyl]pyrrole-2-carboxamide

Compound 34 (1.18 g) was prepared similarly as described for compound33, using (R)-(−)-2-aminobutane instead of iPrNH₂. Method A; Rt: 1.87min. m/z: 384.1 (M−H)⁻ Exact mass: 385.1. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.76 (t, J=7.4 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.29-1.42 (m, 2H),2.28 (d, J=1.8 Hz, 3H), 3.00-3.12 (m, 1H), 3.91 (s, 3H), 7.15 (d, J=7.7Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.42 (d, J=5.7 Hz, 1H), 7.54 (d, J=1.8Hz, 1H), 7.67 (ddd, J=13.0, 7.0, 2.4 Hz, 1H), 10.11 (s, 1H).

Compound 35:N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

3,4-difluoro-5-methyl-aniline (600 mg, 4.2 mmol) dissolved in toluene(20 mL) was added dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (1.0 g) in toluene(50 mL) at reflux. The reaction mixture was refluxed 2 hour, allowed tocool to room temperature and concentrated in vacuo. A mixture of3-methyl-3-oxetanamine hydrochloride (570 mg, 4.6 mmol) and DIPEA (1.8mL, 10.5 mmol) dissolved in CH₂Cl₂ (100 mL) was added and the reactionmixture was stirred overnight and next concentrated in vacuo. Theobtained residue was dissolved in hot methanol (200 mL) and H₂O wasadded. The formed precipitate was filtered off and dried in vacuo,resulting in compound 35 (1.1 g) as a white powder. Method A; Rt: 1.66min. m/z: 398.1 (M−H)⁻ Exact mass: 399.1. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.54 (s, 3H), 2.28 (d, J=2.0 Hz, 3H), 3.91 (s, 3H), 4.14 (d, J=6.4Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.33 (d, J=1.8 Hz, 1H), 7.41 (d, J=5.9Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1H),7.96 (s, 1H), 10.13 (s, 1H).

Compound 36:N-(3,4-difluoro-5-methyl-phenyl)-4-[[(1R)-2-hydroxy-1-methyl-ethyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide

3,4-difluoro-5-methyl-aniline (600 mg, 4.2 mmol) dissolved in toluene(20 mL) was added dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (353 mg) in toluene(100 mL) at reflux. The reaction mixture was refluxed 2 hours, allowedto cool to room temperature and concentrated in vacuo. D-alaninol (787mg, 10.5 mmol) in CH₂Cl₂ (100 mL) was added, followed by CH₃CN (50 mL)and the reaction mixture was stirred overnight and next concentrated invacuo. The obtained residue was dissolved in warm methanol (50 mL) andH₂O was added. The formed precipitate was filtered off and dried invacuo, resulting in compound 36 (1.16 g).

Method A; Rt: 1.57 min. m/z: 386.0 (M−H)⁻ Exact mass: 387.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.98 (d, J=6.2 Hz, 3H), 2.28 (d, J=2.0 Hz, 3H),3.07-3.20 (m, 2H), 3.32-3.39 (m, 1H), 3.91 (s, 3H), 4.65 (t, J=5.5 Hz,1H), 7.10 (d, J=6.8 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.42 (d, J=5.9 Hz,1H), 7.55 (d, J=1.8 Hz, 1H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1H), 10.13(s, 1H).

Compound 37:N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]-sulfamoyl]pyrrole-2-carboxamide

Compound 37 was prepared similarly as described for compound 35, using(S)-(−)-3-aminotetrahydrofuran p-toluenesulfonate instead of3-methyl-3-oxetanamine hydrochloride. After reaction, the obtainedresidue was dissolved in EtOAc (300 mL), washed with 1M HCl (2×), waterand saturated NaHCO₃. The solution was dried over magnesium sulphate,filtered and concentrated. The obtained residue was recrystallized fromhot methanol (50 mL) upon addition of water. Compound 37 (464 mg) wasobtained as white fluffy crystals after drying in vacuo. Method A; Rt:1.65 min. m/z: 398.1 (M−H)⁻ Exact mass: 399.1. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.66-1.77 (m, 1H), 1.90-2.03 (m, 1H), 2.28 (d, J=1.8 Hz, 3H),3.40-3.47 (m, 1H), 3.61 (td, J=8.0, 5.9 Hz, 1H), 3.66-3.76 (m, 3H), 3.92(s, 3H), 7.33 (d, J=2.0 Hz, 1H), 7.41 (d, J=5.9 Hz, 1H), 7.56 (d, J=5.5Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.66 (ddd, J=12.9, 7.0, 2.5 Hz, 1H),10.14 (s, 1H).

Compound 38:4-(tert-butylsulfamoyl)-N-(3,4-difluoro-5-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

Compound 38 (399 mg) was prepared similarly as described for compound33, using tert-butylamine instead of iPrNH₂. Method A; Rt: 1.86 min.m/z: 384.1 (M−H)⁻ Exact mass: 385.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.17 (s, 9H), 2.28 (d, J=2.0 Hz, 3H), 3.90 (s, 3H), 7.11 (s, 1H), 7.31(d, J=1.8 Hz, 1H), 7.38-7.44 (m, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.66 (ddd,J=1.0 Hz, 1H), 10.11 (s, 1H).

Compound 39:N-[3-(difluoromethyl)-4-fluoro-phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

To 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (1.6 g) intoluene (100 mL) at reflux, 3-(difluoromethyl)-4-fluoro-aniline (1equiv) was added dropwise (0.1 mL/min). After addition, the mixture wasfurther refluxed for 15 minutes. The reaction mixture, containing5-[[3-(difluoromethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride was allowed to reach room temperature and was used as such inthe next step. To half of the above obtained solution containing5-[[3-(difluoromethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride, 3-methyl-3-oxetanamine hydrochloride (449 mg, 3.6 mmol) andDIPEA (1.14 mL, 6.6 mmol) dissolved in CH₂Cl₂ (5 mL) were added and thereaction mixture was stirred overnight. More DIPEA (1.14 mL, 6.6 mmol)was added and the mixture was stirred over weekend. The volatiles wereremoved under reduced pressure and the residue was purified on silicausing a heptane to EtOAc gradient yielding compound 39 (681 mg) as awhite powder. Method C; Rt: 1.60 min. m/z: 416.1 (M−H)⁻ Exact mass:417.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.92 (s, 3H), 4.14(d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.22 (t, J=54.4 Hz, 1H),7.32-7.40 (m, 2H), 7.59 (d, J=1.8 Hz, 1H), 7.84-7.93 (m, 1H), 7.96 (s,1H), 8.05 (dd, J=6.3, 2.5 Hz, 1H), 10.25 (s, 1H).

Compound 40:N-[3-(difluoromethyl)-4-fluoro-phenyl]-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 40 (670 mg) was prepared similarly as described for compound 39using D-alaninol instead of 3-methyl-3-oxetanamine hydrochloride. MethodC; Rt: 1.50 min. m/z: 404.0 (M−H)⁻ Exact mass: 405.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.98 (d, J=6.2 Hz, 3H), 3.05-3.21 (m, 2H), 3.33-3.38 (m,1H), 3.92 (s, 3H), 4.66 (t, J=5.5 Hz, 1H), 7.10 (d, J=6.8 Hz, 1H), 7.22(t, J=54.4 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.36 (t, J=9.5 Hz, 1H), 7.56(d, J=1.5 Hz, 1H), 7.89 (dd, J=8.8, 3.3 Hz, 1H), 8.06 (dd, J=6.3, 2.5Hz, 1H), 10.26 (s, 1H).

Compound 41:N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 41 (376 mg) was prepared similarly as described for compound 40using 4-fluoro-3-(trifluoromethyl)aniline instead of3-(difluoromethyl)-4-fluoro-aniline.

Method B; Rt: 0.93 min. m/z: (M−H)⁻ Exact mass: 423.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.98 (d, J=6.2 Hz, 3H), 3.07-3.20 (m, 2H), 3.34-3.39 (m,1H), 3.92 (s, 3H), 4.66 (t, J=5.5 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H), 7.35(d, J=1.8 Hz, 1H), 7.50 (t, J=9.9 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H),7.99-8.08 (m, 1H), 8.20 (dd, J=6.6, 2.6 Hz, 1H), 10.34 (s, 1H).

Compound 42:N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole-2-carboxamide

Compound 42 (569 mg) was prepared similarly as described for compound41, using (S)-(−)-3-aminotetrahydrofuran-4-toluene-sulfonate instead ofD-alaninol. Method C; Rt: 1.77 min. m/z: 434.1 (M−H)⁻ Exact mass: 435.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.77 (m, 1H), 1.91-2.04 (m, 1H),3.40-3.48 (m, 1H), 3.61 (td, J=8.0, 5.9 Hz, 1H), 3.66-3.77 (m, 3H), 3.93(s, 3H), 7.36 (d, J=2.0 Hz, 1H), 7.50 (t, J=9.8 Hz, 1H), 7.57 (d, J=5.7Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.99-8.07 (m, 1H), 8.20 (dd, J=6.4, 2.6Hz, 1H), 10.35 (s, 1H).

Compound 43:N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

Compound 43 (164 mg) was prepared similarly as described for compound41, using 3-methyl-3-oxetanamine hydrochloride instead of D-alaninol.After silica gel column chromatography, the compound was recrystallizedfrom MeOH. Method A; Rt: 1.73 min. m/z: 434.0 (M−H)⁻ Exact mass: 435.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.92 (s, 3H), 4.14 (d,J=6.2 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.50 (t,J=9.8 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.97 (s, 1H), 7.99-8.07 (m, 1H),8.20 (dd, J=6.5, 2.5 Hz, 1H), 10.34 (s, 1H).

Compound 44:N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

Compound 44 (146 mg) was prepared similarly as described for compound41, using isopropylamine instead of D-alaninol. After silica gel columnchromatography, the compound triturated with MeOH and diisopropylether,resulting in compound 44 as a white solid. Method B; Rt: 1.06 min. m/z:406.1 (M−H)⁻ Exact mass: 407.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d,J=6.6 Hz, 6H), 3.22-3.29 (m, 1H), 3.92 (s, 3H), 7.20 (d, J=7.0 Hz, 1H),7.35 (d, J=2.0 Hz, 1H), 7.50 (t, J=9.8 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H),7.98-8.07 (m, 1H), 8.20 (dd, J=6.4, 2.6 Hz, 1H), 10.33 (s, 1H).

Compound 45:N-[3-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (800 mg) wasdissolved in toluene (25 mL) and brought to reflux.3-amino-5-fluorobenzotrifluoride (592 mg, 3.3 mmol) was added dropwise.After addition the reaction was refluxed for 4 hours. The reactionmixture was allowed to reach room temperature and 3-methyl-3-oxetanaminehydrochloride (408 mg, 3.3 mmol) and DIPEA (1.4 mL, 8.3 mmol) dissolvedin CH₂Cl₂ (2 mL) were added and the reaction mixture was stirredovernight. More 3-methyl-3-oxetanamine hydrochloride (0.5 equiv) andDIPEA (0.5 equiv) in CH₂Cl₂ (2 mL) was added and the reaction mixturewas stirred 2 hours more. The reaction mixture was brought to 50° C. andstirred for 2 hours. The volatiles were removed under reduced pressureand the residue was redissolved in EtOAc (30 mL). The formedprecipitates were filtered off and the filtrate was evaporated todryness. The obtained residue was triturated in MeOH (15 mL), filteredand dried in vacuo, yielding compound 45 (704 mg) as a white powder.Method B; Rt: 1.05 min. m/z: 434.2 (M−H)⁻ Exact mass: 435.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.93 (s, 3H), 4.14 (d, J=6.4 Hz, 2H),4.60 (d, J=6.2 Hz, 2H), 7.37 (d, J=8.6 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H),7.64 (d, J=1.8 Hz, 1H), 7.91-8.02 (m, 3H), 10.46 (s, 1H).

Compound 46:N-(3-bromo-4,5-difluoro-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

3-bromo-4,5-difluoroaniline (2.6 g, 12.8 mmol) in toluene (20 mL) wasadded dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (3100 mg, 12.8mmol) in toluene (160 mL) at reflux. The reaction mixture was refluxed 2hours and next allowed to cool to room temperature. To one third of theabove mixture containing5-[(3-bromo-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride, Isopropylamine (7.3 mL, 85.4 mmol) and DIPEA (2.2 mL, 12.8mmol) in CH₂Cl₂ (70 mL) was added. The reaction mixture was stirred atroom temperature. After a few seconds the homogeneous mixture became asuspension. The solids were filtered, washed with CH₂Cl₂ (4 mL) anddried overnight in vacuo resulting in compound 46 (1.02 g) as an offwhite powder. Method B; Rt: 1.10 min. m/z: 436.1 (M−H)⁻ Exact mass:437.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.6 Hz, 6H), 3.14-3.30(m, 1H), 3.92 (s, 3H), 7.22 (d, J=7.0 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H),7.57 (d, J=1.8 Hz, 1H), 7.74-7.95 (m, 2H), 10.27 (s, 1H).

Compound 47:N-(3-bromo-4,5-difluoro-phenyl)-1-methyl-4-[[(1R)-1-methylpropy]-sulfamoyl]pyrrole-2-carboxamide

Compound 47 was prepared similarly as described for compound 46 using(R)-(−)-2-aminobutane (4 equiv) instead of isopropylamine. Afteraddition of (R)-(−)-2-aminobutane, the mixture was stirred overnight.The solid was filtered, washed with CH₂Cl₂ and dried in vacuo, resultingin compound 47 (1.17 g) as an off-white solid. Method B; Rt: 1.15 min.m/z: 448.0 (M−H)⁻ Exact mass: 449.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.76 (t, J=7.5 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.24-1.46 (m, 2H), 3.07(spt, J=6.7 Hz, 1H), 3.91 (s, 3H), 7.17 (d, J=7.5 Hz, 1H), 7.33 (d,J=1.8 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.78-7.95 (m, 2H), 10.26 (s, 1H).

Compound 48:N-(3-bromo-4,5-difluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

Compound 48 was prepared similarly as described for compound 46 using3-methyl-3-oxetanamine (4 equiv) instead of isopropylamine. Afteraddition of 3-methyl-3-oxetanamine, the mixture was stirred for 5 days.The formed precipitate was filtered, washed with CH₂Cl₂ and dried invacuo, resulting in compound 48 (707 mg) as an off white powder. MethodB; Rt: 1.00 min. m/z: 464.0 (M−H)⁻ Exact mass: 465.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.59(d, J=6.2 Hz, 2H), 7.35 (d, J=2.0 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.84(td, J=6.3, 2.5 Hz, 1H), 7.89 (ddd, J=7.7, 5.1, 2.4 Hz, 1H), 7.98 (br.s., 1H), 10.28 (br. s., 1H).

Compound 49: methyl2-[[5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]sulfonylamino]-2-methyl-propanoate

5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1.96 g) was stirred in CH₂Cl₂ (90 mL). DIPEA (1.0 mL, 5.9mmol) and alpha-aminoisobutyric acid methyl ester hydrochloride (1 g,6.5 mmol) were added under N₂-atmosphere at room temperature. Thereaction mixture was stirred for 3 hour. More DIPEA (2 mL) was added andthe reaction mixture was stirred for 80 hours. Next, the reactionmixture was washed with 1M HCl (100 mL). The organic layer was dried onNa₂SO₄. After evaporation of the solvent, the residue was purified bysilica gel column chromatography (EtOAc/Heptane 0/100 to 100/0). Thedesired fractions were combined, the solvent was evaporated and theobtained solid dried in vacuo. Compound 49 (1.6 g) was obtained as awhite solid. Method A; Rt: 1.70 min. m/z: 410.1 (M−H)⁻ Exact mass:411.1. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.35 (s, 6H), 2.23 (d, J=1.1 Hz,3H), 3.54 (s, 3H), 3.90 (s, 3H), 7.10 (t, J=9.1 Hz, 1H), 7.29 (d, J=1.5Hz, 1H), 7.48-7.56 (m, 2H), 7.65 (dd, J=7.0, 2.6 Hz, 1H), 7.85 (s, 1H),10.04 (s, 1H).

Synthesis of1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylic acid

Chlorosulfonic acid (80 mL) was cooled to 0° C. and methyl1-methylpyrrole-2-carboxylate (20 g, 143.73 mmol) was added dropwise.After addition, the mixture was allowed to reach room temperature andstirred for another hour. The resulting mixture was added drop wise to amechanically stirred, temperature controlled, ice-water mixture (1500mL) keeping the temperature under 5° C. A white precipitation wasformed. The obtained aqueous mixture was extracted using dichloromethane(3×500 mL). The combined extracts were dried on sodium sulphate,filtered and concentrated in vacuo yielding methyl4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (29.4 g) as a whitepowder which was used as such. Methyl4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (5 g, 1.04 mmol)was dissolved in acetonitrile (50 mL). diisopropylethylamine (9.06 mL,52.6 mmol) was added, followed by 3-methyl-3-oxetanamine (1.92 g, 22.1mmol) and the resulting mixture was refluxed for 2 hours. Then, themixture was cooled to room temperature and concentrated in vacuo. Theresulting residue was dissolved in dichloromethane (250 mL) and this waswashed with HCl (2×150 mL). The organics were dried on sodium sulphate,filtered and concentrated in vacuo yielding methyl1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylate(6.07 g) as a beige powder which was used as such. Method B; Rt: 0.63min. m/z: 287.1 (M−H)⁻ Exact mass: 288.1. Methyl1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylate(6.07 g, 21.05 mmol) was dissolved in tetrahydrofuran (60 mL). Lithiumhydroxide (0.76 g, 31.58 mmol) in distilled water (8 mL) was added,followed by methanol (3 mL). The resulting mixture was stirred for 72hours. Next, it was concentrated until only water remained and extradistilled water (15 mL) was added. After neutralization withhydrochloric acid (1M/aq/31.6 mL, 31.58 mmol). The resulting mixture wasextracted using 2-methyltetrahydrofuran (3×20 mL). The combined extractswere dried on sodium sulphate, filtered and concentrated in vacuoyielding1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylic acid(5.77 g) as a bright white powder which was used as such. Method B; Rt:0.26 min. m/z: 273.1 (M−H)⁻ Exact mass: 274.1

Compound 50:N-(3-cyano-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

A tube was charged with1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylic acid(0.25 g, 0.91 mmol) and HATU (0.36 g, 0.96 mmol). N,N-dimethylformamide(1 mL) and diisopropylethylamine (0.47 mL, 2.73 mmol) were added and themixture was stirred for 30 minutes. Next, 5-amino-2-fluorobenzonitrile(0.26 g, 1.82 mmol) was added at once and the resulting mixture wasstirred at room temperature for 2 hours. The resulting mixture was addedto distilled water (10 mL) under stirring and the mixture was allowed tostir for 1 hour. A precipitation was formed which was collected on afilter and dried in vacuo, yielding compound 50 (0.25 g) as a whitepowder. Method B; Rt: 0.83 min. m/z: 391.1 (M−H)⁻ Exact mass: 392.1. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92 (s, 3H), 4.14 (d, J=6.2Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.35 (d, J=1.5 Hz, 1H), 7.53 (t, J=9.1Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.93-8.07 (m, 2H), 8.21 (dd, J=5.7, 2.6Hz, 1H), 10.36 (s, 1H).

Compound 51:N-[4-cyano-3-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]-1H-pyrrole-2-carboxamide

A tube was charged with1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylic acid(0.2 g, 0.73 mmol) and HATU (0.29 g, 0.77 mmol). N,N-dimethylformamide(1 mL) and diisopropylethylamine 0.38 mL, 2.19 mmol) were added and themixture was stirred for 30 minutes. To this was added4-amino-2-(trifluoromethyl)benzonitrile (0.27 g, 1.46 mmol) at once andthe resulting mixture was stirred at room temperature for 2 hours. Theresulting mixture was added to distilled water (10 mL) under stirring.The resulting mixture was allowed to stir for 1 hour and then it wasextracted using 2-methyl tetrahydrofuran (3×20 mL). The combinedextracts were dried on sodium sulphate, filtered and concentrated invacuo. The obtained crude was dissolved in dichloromethane (3 mL) andloaded directly on a silica plug. This was purified using columnchromatography (gradient elution EtOAc/heptane 0:100 to 100:0) Thedesired fractions were concentrated in vacuo and dried in vacuo,resulting in compound 51 (18.1 mg) as a bright white powder. Method A;Rt: 1.67 min. m/z: 440.9 (M−H)⁻ Exact mass: 442.1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.94 (s, 3H), 4.14 (d,J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.41-7.46 (m, 1H), 7.62-7.68 (m,1H), 8.00 (br. s., 1H), 8.07-8.14 (m, 1H), 8.16-8.23 (m, 1H), 8.34-8.45(m, 1H), 10.69 (br. s., 1H).

Compound 52:N-(3-cyano-4,5-difluoro-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

A degassed suspension of compound 46 (400 mg, 0.917 mmol), Zn(CN)₂ (93.0mg, 0.79 mmol) and tetrakis(triphenylphosphine)palladium (57.3 mg, 0.050mmol) in DMF (3 mL) was stirred at 75° C. overnight. The mixture wascooled to room temperature and the solids were filtered off and washedwith DMF (2 mL). The filtrate was then poured into water (50 mL). Theprecipitates were filtered and washed with water to afford an off whitepowder. This solid was purified using silica gel column chromatography(ethyl acetate in heptane from 0 to 50%) to afford a white powder (310mg). This white powder is purified using Prep. LCMS. (Hypersyl C18 BDS-3m, 100×4.6 mm) Mobile phase (NH₄HCO₃ 0.2% in water, methanol) thedesired fractions were combined and evaporated to dryness, dissolved inmethanol again and evaporated to dryness and dried in vacuo to affordcompound 52 (27.8 mg) as a white powder. Method B; Rt: 1.01 min. m/z:381.1 (M−H)⁻ Exact mass: 382.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d,J=6.6 Hz, 6H), 3.20-3.30 (m, 1H), 3.92 (s, 3H), 7.23 (br. s., 1H), 7.34(d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.98 (dt, J=4.6, 2.2 Hz, 1H),8.14 (ddd, J=12.9, 7.5, 2.5 Hz, 1H), 10.47 (br. s., 1H).

Compound 53:4-(tert-butylsulfamoyl)-N-(3-cyano-5-fluoro-phenyl)-1-methyl-pyrrole-2-carboxamide

5-amino-3-fluorobenzonitrile (1034 mg, 7.6 mmol) dissolved in toluene(10 mL) was added dropwise during 5 minutes to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (1839 mg, 7.6mmol) in toluene (190 mL) at reflux. The reaction mixture was refluxed 3hours and concentrated in vacuo yielding crude5-[(3-cyano-5-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride as a brown powder which was used as such. (2.74 g). ¹H NMR (400MHz, acetonitrile-d₃) δ ppm 3.97 (s, 3H), 7.24-7.29 (m, 1H), 7.42 (d,J=2.0 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.79-7.86 (m, 2H), 8.93 (br. s,1H). A solution of5-[(3-cyano-5-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (892 mg, 2.48 mmol) and tert-butylamine (544 mg, 7.44 mmol) inacetonitrile (100 mL) were stirred overnight. Water was added untilcrystallisation started. The crystals were filtered of and driedovernight in vacuo at 50° C., resulting in compound 53 (631 mg) MethodA, Rt: 1.74 min m/z: 377.1 (M−H)⁻ Exact mass: 378.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.17 (s, 9H), 3.92 (s, 3H), 7.15 (s, 1H), 7.37 (d, J=2.0Hz, 1H), 7.52-7.56 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.96 (d, J=11.2 Hz,1H), 7.99-8.01 (m, 1H), 10.44 (s, 1H).

Compound 54:N-(3-cyano-5-fluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

A solution of5-[(3-cyano-5-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (924 mg, 2.57 mmol) and 3-methyl-3-oxetanamine (559 mg, 6.4mmol) in acetonitrile (100 mL) was stirred overnight. Water was addeduntil crystallisation started. The crystals were filtered of and driedovernight in vacuo at 50° C., resulting in compound 54 (630 mg) MethodA, Rt: 1.52 min m/z: 391.1 (M−H)⁻ Exact mass: 392.1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.93 (s, 3H), 4.14 (d,J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.52-7.58(m, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.93-7.98 (m, 1H), 7.98-8.01 (m, 2H),10.46 (s, 1H).

Compound 55:N-(3-cyanophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

3-aminobenzonitrile (360 mg, 3.0 mmol) dissolved in toluene (10 mL) wasadded dropwise to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (752 mg, 3.1 mmol)in toluene (90 mL) at reflux. The reaction mixture was refluxed 2.5hours, decanted hot and concentrated in vacuo yielding crude5-[(3-cyanophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride. Asolution of 3-methyloxetan-3-amine (0.271 g, 3.11 mmol) in CH₃CN (10 mL,p.a. dried on molecular sieves) was added to a stirring solution of5-[(3-cyanophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride (1.00g, 3.11 mmol) in CH₃CN (40 mL, p.a. dried on molecular sieves). DIPEA(1.07 mL, 6.21 mol) was added, and the reaction mixture was stirred atroom temperature for 18 hours. The volatiles were evaporated. Theresidue was purified by silica gel column chromatography usingEtOAc-heptane 0/100 to 100/0 as eluent. The desired fractions werecombined and evaporated. The residue was stirred in CH₂Cl₂ (4 mL),filtered off, washed with CH₂Cl₂ (3×), and dried in vacuo at 50° C.,resulting in compound 55 (0.43 g). Method A; Rt: 1.42 min. m/z: 373.0(M−H)⁻ Exact mass: 374.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H),3.93 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.38 (d,J=2.0 Hz, 1H), 7.50-7.59 (m, 2H), 7.61 (d, J=1.5 Hz, 1H), 7.85-8.10 (m,2H), 8.16-8.24 (m, 1H), 10.00-10.67 (m, 1H).

Compound 56:N-(2,6-dideuterio-4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

4-fluoro-3-methyl-aniline (1386 mg, 11.075 mmol), 1M DCl (2075 mg,11.075 mmol) in 11 mL D₂O was heated in the microwave at 180° C. during30 minutes. The reaction mixture was diluted with distilled water (50mL), alkalanised with 1M NaOH, diluted with brine until productseparates as oil and extracted with Et₂O. The organic layer was driedover magnesium sulphate, filtered and concentrated yielding2,6-dideuterio-4-fluoro-3-methyl-aniline (1068 mg) as a light browncolored oil which used as such.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.09 (d, J=2.0 Hz, 3H), 4.79 (br. s.,2H), 6.75 (d, J=9.9 Hz, 1H). 2,6-dideuterio-4-fluoro-3-methyl-aniline(1068 mg, 8.40 mmol) dissolved in toluene (10 mL) was added dropwiseduring 5 minutes to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (2033 mg, 8.40mmol) in toluene (210 mL) at reflux. The reaction mixture was refluxed90 minutes and concentrated in vacuo yielding crude5-[(2,6-dideuterio-4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride as a grey powder which was used as such. (2810 mg). Method A;Rt: 1.91 min m/z: 331.0 (M−H)⁻ Exact mass: 332.0. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.30 (d, J=2.0 Hz, 3H), 4.05 (s, 3H), 7.01 (d, J=9.2Hz, 1H), 7.14 (d, J=1.8 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.57 (br. s.,1H). 3-methyl-3-oxetanamine (491 mg, 5.63 mmol) and DIPEA (0.97 mL, 5.63mmol) were added to a solution of5-[(2,6-dideuterio-4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (750 mg, 2.25 mmol) in dichloromethane (100 mL) and stirredovernight and concentrated in vacuo at 50° C. The residue was dissolvedin EtOAc (150 mL), washed twice with 1M HCl, water and saturated NaHCO₃solution. The solution was dried over sodium sulphate, filtered andconcentrated. The residue was dissolved in warm EtOAc (75 mL) and theproduct crystallized upon addition of heptane (350 mL) The whitecrystals were filtered off and dried overnight in vacuo at 50° C.,resulting in compound 56 (532 mg). Method A, Rt: 1.56 min m/z: 382.1(M−H)⁻ Exact mass: 383.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H),2.23 (d, J=2.0 Hz, 3H), 3.91 (s, 3H), 4.13 (d, J=6.4 Hz, 2H), 4.60 (d,J=5.9 Hz, 2H), 7.09 (d, J=9.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.56 (d,J=1.8 Hz, 1H), 7.94 (s, 1H), 10.02 (s, 1H).

Compound 57:N-(3-chloro-4,5-difluoro-phenyl)-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

3-chloro-4,5-difluorobenzoic acid (1011 mg, 52.5 mmol) was dissolved intert-butyl alcohol (200 mL). Triethylamine (8 mL, 57.8 mmol) was addedfollowed by diphenylphosphoryl azide (14.74 g, 53.6 mmol) and thereaction mixture was refluxed overnight. The reaction mixture wasconcentrated and purified by column chromatography on silica using agradient from 10 till 100% EtOAc in heptane and again with 10% CH₂Cl₂ inheptane till 100% CH₂Cl₂. The product fractions were concentrated invacuo yielding tert-butyl N-(3-chloro-4,5-difluoro-phenyl)carbamate as awhite powder (10.68 g). Method A. Rt: 2.09 min m/z: 262.0 (M−H)⁻ Exactmass: 263.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (s, 9H), 7.37-7.57 (m,2H), 9.74 (s, 1H). HCl (6 M in iPrOH) (20 mL, 120 mmol) was added totert-butyl N-(3-chloro-4,5-difluoro-phenyl)carbamate (10.68 g, 40.5mmol) dissolved in dichloromethane (200 mL) and stirred overnight. Thereaction mixture was concentrated. The white solid residue was dissolvedin water (100 mL), alkalanised with NaOH 1M and extracted with ether.The organic layer was dried over MgSO₄, filtered and concentratedyielding 3-chloro-4,5-difluoro-aniline (6.53 g) as a colorless oil whichwas stored under nitrogen in the dark. ¹H NMR (400 MHz, DMSO-d₆) δ ppm5.53 (s, 2H), 6.34-6.61 (m, 2H).

3-chloro-4,5-difluoro-aniline (3.43 g, 20.95 mmol) dissolved in toluene(10 mL) was added dropwise during 5 minutes to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (5.07 g, 20.95mmol) in toluene (525 mL) at reflux. The reaction mixture was refluxed90 minutes and then concentrated in vacuo yielding crude5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (7.83 g) as a brown powder which was used as such. A mixture of5-[(3-chloro-4,5-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1002 mg, 2.58 mmol) and isopropylamine (457 mg, 7.73 mmol) inacetonitrile (100 mL) was stirred 60 minutes. Water was added untilcrystallisation began. The beige crystals were filtered off and dried invacuo overnight at 50° C., resulting in compound 57 (706 mg). Method A,Rt: 1.88 min m/z: 390.0 (M−H)⁻ Exact mass: 391.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.02 (d, J=6.6 Hz, 6H), 3.20-3.30 (m, 1H), 3.92 (s, 3H),7.22 (d, J=6.8 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H),7.75-7.87 (m, 2H), 10.29 (s, 1H).

Compound 58:4-(tert-butylsulfamoyl)-N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1008 mg, 2.59 mmol), tert-butylamine (569 mg, 7.78 mmol) inacetonitrile (100 mL) was stirred 60 minutes. Water was added untilcrystallisation began. The beige crystals were filtered off and dried invacuo overnight at 50° C., resulting in compound 58 (773 mg) Method A:Rt: 1.95 min m/z: 404.0 (M−H)⁻ Exact mass: 405.1 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.17 (s, 9H), 3.91 (s, 3H), 7.14 (s, 1H), 7.33 (d, J=1.8Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.76-7.86 (m, 2H), 10.28 (s, 1H).

Compound 59:N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1.0 g, 2.57 mmol) 3-methyl-3-oxetanamine (560 mg, 6.43 mmol)and acetonitrile (100 mL) was refluxed 30 minutes. The reaction mixturewas cooled to 20° C. and diluted with water (350 mL). The productcrystallized, was filtered off and dried in vacuo overnight yieldingcompound 59 as a beige powder (677 mg). Method A, Rt: 1.77 min m/z:418.0 (M−H)⁻ Exact mass: 419.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s,3H), 3.92 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=6.2 Hz, 2H), 7.34(d, J=2.0 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.74-7.87 (m, 2H), 7.98 (s,1H), 10.30 (s, 1H).

Compound 60:N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1008 mg, 2.59 mmol), (R)-1,1,1-trifluoro-2-propylamine (1026mg, 9.07 mmol) in acetonitrile (100 mL) was refluxed overnight. Waterwas added until crystallisation started. The beige crystals werefiltered of and dried overnight in vacuo at 50° C., resulting incompound 60 (673 mg). Method A Rt: 1.92 min m/z: 444.0 (M−H)⁻ Exactmass: 445.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H),3.83-4.01 (m, 4H), 7.36 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H),7.75-7.87 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 10.32 (s, 1H).

Alternative Synthesis of Compound 60:

1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (8.0 g, 26.7 mmol), HATU (12.7 g, 33.3 mmol), Et₃N (9.3 mL, 66.6mmol) and 3-chloro-4,5-difluoro-aniline (5.44 g, 33.3 mmol) in DMF (30mL) was stirred overnight at room temperature. The solution wassubjected directly to column chromatography on a 330 g Reveleriscartridge in a Biotage system using a gradient from 10 till 100% EtOAcin heptane. The product fractions were concentrated and purified againin the same way. The product fractions were concentrated, dissolved inwarm EtOAc en the product crystallized upon addition of heptane. Thewhite crystals were filtered off and dried over weekend in vacuo at 50°C. The crystals (7.97 g) were dissolved in warm methanol (150 mL) andthe product crystallized upon addition of water. The product wasfiltered off and dried in vacuo at 50° C. overnight, resulting incompound 60 (7.44 g). [α]₃₆₅ ²⁰=−9.5° (c 1.30 w/v %, MeOH). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 204.6°C.

Compound 65:N-(3-chloro-4,5-difluoro-phenyl)-4-[(3,3-difluoro-1-methyl-cyclo-butyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (622 mg, 1.69 mmol) 3,3-difluoro-1-methyl-cyclobutanaminehydrochloride (306 mg, 2.527 mmol), DIPEA (0.87 mL, 5.06 mmol) andacetonitrile (100 mL) was refluxed 60 minutes. The reaction mixture wasconcentrated and the obtained residue was dissolved in EtOAc (100 mL),washed with 1M HCl, dried over sodium sulphate, filtered andconcentrated. The obtained residue was dissolved in acetonitrile (50mL). Water was added until precipitation was observed. The mixture wasallowed to triturate further overnight. The beige crystals were filteredoff and dried in vacuo at 50° C., resulting in compound 65 (473 mg).Method A; Rt: 1.89 min. m/z: 452.0 (M−H)⁻ Exact mass: 453.0. ¹H NMR (400MHz, acetonitrile-d₃) δ ppm 1.46 (s, 3H), 2.44-2.59 (m, 2H), 2.78-2.94(m, 2H), 3.92 (s, 3H), 5.89 (s, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.36 (d,J=2.0 Hz, 1H), 7.59 (dt, J=5.8, 2.4 Hz, 1H), 7.65 (ddd, J=12.4, 6.8, 2.6Hz, 1H), 8.64 (br. s., 1H).

Compound 66:N-(3-chloro-4,5-difluoro-phenyl)-4-(1,1-dimethylpropylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (572 mg, 1.472 mmol), tert-amylamine (327 mg, 3.68 mmol) inacetonitrile (75 mL) was stirred 48 hours. Water was added untilcrystallisation began. The crystals were filtered off and dried in vacuoat 50° C., resulting in compound 66 (356 mg). Method A; Rt: 2.09 min.m/z: 418.1 (M−H)⁻ Exact mass: 419.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.78 (t, J=7.4 Hz, 3H), 1.12 (s, 6H), 1.49 (q, J=1.0 Hz, 2H), 3.91 (s,3H), 7.01 (s, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H),7.75-7.87 (m, 2H), 10.28 (s, 1H).

Compound 72:N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[[1-(trifluoromethyl)-cyclopropyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1274 mg, 3.28 mmol), 1-(trifluoromethyl)cyclopropanamine (1000mg, 7.99 mmol) and triethylamine (0.57 mL, 4.1 mmol) in acetonitrile(100 mL) was refluxed overnight. An equal amount of1-(trifluoromethyl)cyclopropanamine was added and the reaction mixturewas further refluxed overnight. The reaction mixture was concentrated.The residue was dissolved in EtOAc (100 mL), washed with 1M HCl, driedover sodium sulphate, filtered and concentrated. The residue waspurified by column chromatography on silica using a gradient from 10 to100% EtOAc in heptane. The pure fractions were concentrated yieldingcompound 72 (42.4 mg) as a powder. Method A; Rt: 1.95 min. m/z: 456.0(M−H)⁻ Exact mass: 457.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.22 (m,4H), 3.91 (s, 3H), 7.31 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H),7.74-7.86 (m, 2H), 8.74 (s, 1H), 10.30 (s, 1H).

Compound 73:N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[[2,2,2-trifluoro-1-(methoxymethyl)-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (318 mg, 0.817 mmol),1,1,1-trifluoro-3-methoxy-2-methyl-propan-2-amine hydrochloride (237 mg,1.23 mmol) and triethylamine (0.34 mL, 1.45 mmol) in acetonitrile (7 mL)was heated in a microwave oven at 150° C. during 30 minutes. Thereaction mixture was concentrated. The residue was dissolved in water(50 mL) and washed with 1M HCl. The organic layer was dried over sodiumsulphate, filtered and concentrated. The residue was subjected to columnchromatography on silica using a gradient from 10 to 100% EtOAc inheptane. The product fractions were concentrated and the residue wascrystallized by dissolving in methanol (5 mL) upon addition of water.The crystals were filtered off and dried overnight in vacuo at 50° C.,resulting in compound 73 (17.8 mg). Method A; Rt: 1.97 min. m/z: 488.0(M−H)⁻ Exact mass: 489.0. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.41 (s, 3H),3.23 (s, 3H), 3.46 (s, 2H), 3.92 (s, 3H), 7.34 (d, J=1.8 Hz, 1H), 7.60(d, J=1.8 Hz, 1H), 7.74-7.89 (m, 2H), 8.04 (s, 1H), 10.34 (s, 1H).

Compound 96:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

2,2,2-trifluoro-1,1-dimethyl-ethylamine (0.344 g, 2.71 mmol) wasdissolved in pyridine (10 mL, dried on molecular sieves) under N₂-atm.5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.5 g, 1.35 mmol) was added. The reaction mixture was stirredat room temperature for 20 hours. The reaction mixture was treated withHCl 1M (100 mL) and extracted with EtOAc. The combined organic layer waswashed with water followed by saturated NaHCO₃, dried with Na₂SO₄ andthe solvent was evaporated. The residue was dissolved in CH₂Cl₂ (5 mL)and the formed precipitate was filtered off and washed with CH₂Cl₂ (2×5mL). The filtrate was concentrated and the obtained residue was purifiedby silica gel chromatography (EtOAc-heptane 0/100 to 100/0) and furtherpurified by reverse phase column chromatography, resulting in compound96 (45 mg) as a white solid. Method A; Rt: 2.03 min. m/z: 457.9 (M−H)⁻Exact mass: 459.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 6H), 3.92(s, 3H), 7.34 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.75-7.89 (m, 2H), 8.08(br. s., 1H), 10.33 (br. s., 1H).

Compound 61:2-[[5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]-sulfonylamino]-2-methyl-propanoicacid

LiOH (0.567 g, 13.5 mmol) was dissolved in water (20 mL) and addeddropwise to a mixture of compound 49 (1.39 g, 3.38 mmol) in MeOH (40mL). The reaction mixture was stirred at 50° C. for 7 hour. Then HCl 1N(15 mL, 15.2 mmol) was added dropwise After 16 hour without stirring thewhite precipitate was filtered off, washed with Methanol/Water (2:1;2×60 mL). The white solid was dried in vacuo at 50° C. resulting incompound 61 (1.09 g). Method A; Rt: 1.19 min. m/z: 396.0 (M−H)⁻ Exactmass: 397.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6H), 2.22 (d,J=1.5 Hz, 3H), 3.89 (s, 3H), 7.05-7.13 (m, 1H), 7.30 (d, J=1.8 Hz, 1H),7.45-7.55 (m, 2H), 7.57-7.68 (m, 2H), 10.01 (s, 1H), 12.42-12.58 (m,1H).

Compound 62:4-[[1,1-dimethyl-2-(methylamino)-2-oxo-ethyl]sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

1,1′-carbonyldiimidazole (CDI, 0.326 g, 2.013 mmol) was added to astirring solution of compound 61 (0.32 g, 0.805 mmol) in acetonitriledried on molecular sieves (10 mL). The reaction mixture was stirred in asealed tube at room temperature for 2 hour. Next, methylamine (2M inMethanol, 4.0 mL, 8.1 mmol) was added. The reaction mixture was stirredfor 2.5 hour at room temperature. The solvent and the excess ofmethylamine were removed and the mixture was purified by silica gelcolumn chromatography (EtOAc/Heptane 0/100 to 100/0). The desiredfractions were combined and the solvent was evaporated and dried invacuo resulting in compound 62 (221 mg) as a white solid. Method A; Rt:1.49 min. m/z: 409.0 (M−H)⁻ Exact mass: 410.1. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.30 (s, 6H), 2.23 (d, J=1.5 Hz, 3H), 2.53 (d, J=4.6 Hz, 3H), 3.89(s, 3H), 7.06-7.13 (m, 1H), 7.27-7.30 (m, 1H), 7.32-7.36 (m, 1H),7.43-7.48 (m, 1H), 7.50-7.54 (m, 2H), 7.61-7.66 (m, 1H), 9.97-10.04 (m,1H).

Compound 63:4-[[2-(dimethylamino)-1,1-dimethyl-2-oxo-ethyl]sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

1,1′-carbonyldiimidazole (CDI, 0.149 g, 0.921 mmol) was added to astirring mixture of compound 61 (0.366 g, 0.921 mmol) in acetonitrile ina sealed tube under N₂ atmosphere. The resultant solution was stirred atroom temperature for 18 hours. Then, more (CDI, 0.224 g, 1.381 mmol) wasadded and the mixture was further stirred for 2 hours. An excess ofdimethylamine was added (10 drops out of a pressure bottle). Thereaction mixture was stirred at room temperature for 5 h. Theprecipitate was filtered off, washed with AcCN (1×2 mL) and the solidwas dried at 50° C. in vacuo yielding compound 63 (323 mg) as a a whitepowder. Method A; Rt: 1.51 min. m/z: 423.2 (M−H)⁻ Exact mass: 424.2. ¹HNMR (400 MHz, DMSO-d₆, 100° C.) δ ppm 1.39 (s, 6H), 2.22 (d, J=1.8 Hz,3H), 2.97 (s, 6H), 3.91 (s, 3H), 7.02 (t, J=9.2 Hz, 1H), 7.25 (d, J=1.8Hz, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.45-7.52 (m, 1H), 7.58 (dd, J=7.0, 2.4Hz, 1H), 9.74 (br. s., 1H).

Compound 64:4-[(2-amino-1,1-dimethyl-2-oxo-ethyl)sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

1,1′-carbonyldiimidazole (CDI, 0.295 g, 1.820 mmol) was added to astirring mixture of compound 61 (0.289 g, 0.727 mmol) in acetonitrile ina sealed tube under N₂ atmosphere and stirred 3 hours. The reactionmixture was added dropwise to 7M NH₃ in methanol (25 mL). The solventwas evaporated leaving a yellow oil which was purified by silica gelcolumn chromatography (EtOAc/Heptane 0/100 to 100/0). The desiredfractions were combined and the solvent was evaporated and dried invacuo resulting in compound 64 (123 mg) as a solid. Method A; Rt: 1.44min. m/z: 395.0 (M−H)⁻ Exact mass: 396.1. ¹H NMR (400 MHz, DMSO-d₆, 60°C.) δ ppm 1.35 (s, 6H), 2.22 (d, J=1.8 Hz, 3H), 3.90 (s, 3H), 6.91 (br.s., 2H), 7.02-7.08 (m, 1H), 7.11 (br. s., 1H), 7.30 (d, J=2.0 Hz, 1H),7.47-7.54 (m, 2H), 7.61 (dd, J=7.4, 2.3 Hz, 1H), 9.86 (br. s., 1H).

Compound 67:4-(tert-butylsulfamoyl)-N-(2,6-dideuterio-4-fluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

t-Butylamine (245 mg, 3.35 mmol) was added to a solution of5-[(2,6-dideuterio-4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (372 mg, 1.116 mmol) in acetonitrile (25 mL) and stirredovernight. Water was added until crystallization began. The precipitatewas filtered off and dried in vacuo at 50° C., resulting in compound 67(260 mg) Method A; Rt: 1.76 min. m/z: 368.1 (M−H)⁻ Exact mass: 369.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 2.22 (d, J=2.0 Hz, 3H), 3.90(s, 3H), 7.06-7.11 (m, 2H), 7.29 (d, J=2.0 Hz, 1H), 7.49 (d, J=1.5 Hz,1H), 10.00 (s, 1H).

Compound 68:4-(tert-butylsulfamoyl)-1-methyl-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide

t-Butylamine (498 mg, 6.806 mmol) was added to a solution of1-methyl-5-[(3,4,5-trifluorophenyl)carbamoyl]pyrrole-3-sulfonyl chloride(800 mg, 2.269 mmol) in acetonitrile (50 mL) and stirred 3 hours. Waterwas added until crystallization began. The precipitate was filtered offand dried in vacuo at 50° C. Method A; Rt: 1.91 min. m/z: 388.1 (M−H)⁻Exact mass: 389.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 3.91(s, 3H), 7.14 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H),7.67 (dd, J=10.6, 6.6 Hz, 2H), 10.30 (s, 1H).

Compound 69:N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[2,2,2-trideuterio-1,1-bis(trideuteriomethyl)ethyl]sulfamoyl]pyrrole-2-carboxamide

1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-amine (473 mg,5.76 mmol) was added to a solution of5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (635 mg, 1.92 mmol) in acetonitrile (43 mL) and stirredovernight. Water was added until crystallization began. The precipitatewas filtered off and dried in vacuo at 50° C. Method A; Rt: 1.74 min.m/z: 375.1 (M−H)⁻ Exact mass: 376.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.23 (d, J=1.5 Hz, 3H), 3.90 (s, 3H), 7.04-7.13 (m, 2H), 7.29 (d, J=1.8Hz, 1H), 7.47-7.56 (m, 2H), 7.64 (dd, J=7.2, 2.5 Hz, 1H), 10.00 (s, 1H).

Compound 70:N-(2,6-dideuterio-4-fluoro-3-methyl-phenyl)-1-methyl-4-[[2,2,2-trideuterio-1,1-bis(trideuteriomethyl)ethyl]sulfamoyl]pyrrole-2-carboxamide

1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-amine (377 mg,4.59 mmol) was added to a solution of5-[(2,6-dideuterio-4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (611 mg, 1.84 mmol) in acetonitrile (41 mL) and stirredovernight. Water was added until crystallization began. The precipitatewas filtered off and dried in vacuo at 50° C. Method A; Rt: 1.82 min.m/z: 377.1 (M−H)⁻ Exact mass: 378.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.23 (d, J=2.0 Hz, 3H), 3.90 (s, 3H), 7.05-7.12 (m, 2H), 7.29 (d, J=2.0Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 10.00 (s, 1H).

Compound 71:4-(tert-butylsulfamoyl)-N-(2,6-dideuterio-3,4,5-trifluoro-phenyl)-1-methyl-pyrrole-2-carboxamide

t-Butylamine (331 mg, 4.53 mmol) was added to a solution of5-[(2,6-dideuterio-3,4,5-trifluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (666 mg, 1.51 mmol) (obtained similarly as described in thesynthesis for compound 56, starting from 3,4,5-trifluoroaniline insteadof 4-fluoro-3-methyl-aniline, via2,6-dideuterio-3,4,5-trifluoro-aniline) in acetonitrile (30 mL) andstirred 1 hour. Water was added until crystallization began. Theprecipitate was filtered off and dried overnight in vacuo at 50° C.Method A; Rt: 1.89 min. m/z: 389.9 (M−H)⁻ Exact mass: 391.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 3.91 (s, 3H), 7.14 (s, 1H), 7.32 (d,J=2.0 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 10.30 (s, 1H).

Synthesis of3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid

Sodium hydride (914 mg, 23.87 mmol) was added to a solution of ethyl3-fluoro-1H-pyrrole-2-carboxylate (2885 mg, 18.36 mmol) and iodomethane(3888 mg, 23.9 mmol) in dry DMF (43 mL) and the mixture was stirred for17 hours. The reaction mixture was acidified with 1M HCl andconcentrated. The residue was dissolved in water/EtOAc. The organiclayer was dried over sodium sulphate, filtered and concentrated. Theobtained residue was dissolved in acetonitrile (50 mL), washed withheptane and concentrated yielding a brown liquid of crude ethyl3-fluoro-1-methyl-pyrrole-2-carboxylate, which was used as such.Chlorosulfonic acid (1344 mg, 11.53 mmol) was dissolved indichloromethane (50 mL) and cooled in an icebath. Crude ethyl3-fluoro-1-methyl-pyrrole-2-carboxylate (1880 mg) was added and thereaction mixture was stirred 90 minutes. The reaction mixture wasconcentrated and the brown residual powder was dried for 17 hours invacuo at 50° C. (5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonicacid, 2477 mg) Method A; Rt: 0.76 min. m/z: 250.0 (M−H)⁻ Exact mass:251.0. A mixture of crude5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid (2318 mg) inthionylchloride (20 mL) was heated at 80° C. during 30 minutes. Thesolution was concentrated and the residue (containing ethyl4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate) dissolved inacetonitrile (25 mL). 3-methyloxetan-3-amine (3035 mg, 34.84 mmol)dissolved in acetonitrile (20 mL) was added and the reaction mixture wasstirred 1 hour at room temperature. The reaction mixture wasconcentrated. The obtained residue was dissolved in dichloromethane (200mL), washed with water, dried over sodium sulphate, filtered andconcentrated. The residue was purified by column chromatography onsilica using a gradient from 5 to 100% EtOAc in heptane. The productfractions were concentrated in vacuo yielding ethyl3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(1900 mg) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (t,J=7.2 Hz, 3H), 1.52 (s, 3H), 3.83 (s, 3H), 4.15 (d, J=6.4 Hz, 2H), 4.27(q, J=7.0 Hz, 2H), 4.61 (d, J=5.9 Hz, 2H), 7.57 (d, J=4.6 Hz, 1H), 8.28(s, 1H). A mixture of ethyl3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(1900 mg, 5.93 mmol), lithium hydroxide (426 mg, 17.8 mmol), THF (20 mL)and distilled water (5 mL) was stirred 210 minutes at room temperature.THF was distilled off and the mixture neutralized with 1M HCl (5.9 mL,5.9 mmol). The mixture was extracted with 2-methyltetrahydrofuran (3×100mL). The combined organic layers were dried over sodium sulphate,filtered and concentrated. The resulting white powder was driedovernight in vacuo at 50° C.(3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid, 1710 mg) Method A; Rt: 0.68 min. m/z: 290.9 (M−H)⁻ Exact mass:292.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (s, 3H), 3.82 (s, 3H), 4.15(d, J=6.6 Hz, 2H), 4.61 (d, J=5.9 Hz, 2H), 7.52 (d, J=4.6 Hz, 1H), 8.26(s, 1H), 13.11 (br. s, 1H).

Compound 74:N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide

Triethylamine (0.19 mL, 1.36 mmol) was added to a solution of3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid (133 mg, 0.57 mmol) in DMF (1 mL) followed by HATU (216 mg, 0.57mmol) and stirred 20 minutes. Then 3,4-difluoroaniline (117 mg, 0.91mmol) was added and the reaction mixture stirred overnight. The mixturewas concentrated in vacuo. The residue was mixed with water (10 mL) andextracted with EtOAc (2×30 mL). The organic layer was dried over sodiumsulphate, filtered and concentrated. The obtained residue was purifiedby column chromatography on silica using a gradient from 10 to 100%EtOAc in heptane. The product fractions were concentrated and theremaining white powder was dissolved in warm EtOAc (10 mL) and uponaddition of heptane the compound crystallized. The white crystals werefiltered off and dried in vacuo, resulting in compound 74 (102 mg)Method A; Rt: 1.62 min. m/z: 401.9 (M−H)⁻ Exact mass: 403.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.80 (s, 3H), 4.17 (d, J=6.4 Hz, 2H),4.64 (d, J=6.2 Hz, 2H), 7.35-7.47 (m, 2H), 7.51 (d, J=4.6 Hz, 1H),7.75-7.87 (m, 1H), 8.30 (s, 1H), 10.24 (s, 1H).

Compound 75:N-(3,5-Dichloro-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

3,5-dichloro-4-fluoroaniline (1534 mg, 8.5 mmol) dissolved in toluene(10 mL) was added to 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (2063 mg, 8.52 mmol) in toluene (115 mL) at reflux and refluxed2 hours. The reaction mixture was filtered while still hot and thefiltrate was concentrated, yielding crude5-[(3,5-dichloro-4-fluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride as a crude beige powder which was used as such. ¹H NMR (400MHz, acetonitrile-d₃) δ ppm 3.96 (s, 3H), 7.39 (d, J=2.0 Hz, 1H),7.71-7.77 (m, 3H), 8.78 (br. s., 1H). 3-methyl-3-oxetanamine (407.3 mg,4.68 mmol) was added to crude5-[(3,5-dichloro-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (601 mg) in acetonitrile (57 mL) and stirred overnight. Waterwas added until crystallisation began. The formed white crystals werefiltered off and dried in vacuo at 50° C. during 4 hours. Compound 75was recrystallized from EtOAc upon addition of heptane. The whitecrystals (346 mg) were filtered off and dried in vacuo at 50° C. overweekend. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92 (s, 3H),4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.35 (d, J=2.0 Hz, 1H),7.62 (d, J=1.8 Hz, 1H), 7.95 (d, J=6.2 Hz, 2H), 7.99 (s, 1H), 10.27 (s,1H). Method A; Rt: 1.77 min. m/z: 434.0 (M−H)⁻ Exact mass: 435.0.

Compound 76:4-(tert-Butylsulfamoyl)-N-(3,5-dichloro-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

tert-butylamine (450.6 mg, 6.16 mmol) was added to crude5-[(3,5-dichloro-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (792 mg) in acetonitrile (75 mL) and stirred 2 hours. Water wasadded until crystallisation began. The white crystals were filtered offand dried overnight in vacuo at 50° C., resulting in compound 76 (517mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 3.91 (s, 3H), 7.14(s, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.95 (d, J=6.2Hz, 2H), 10.26 (s, 1H). Method A; Rt: 1.99 min. m/z: 420.0 (M−H)⁻ Exactmass: 421.0.

Compound 77:N-(4-Chloro-3-methylphenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

DIPEA (0.471 mL, 2.73 mol) was added to a stirring mixture of1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(0.25 g, 0.000911 mol) and CH₃CN (5 mL) under N₂-atmosphere. To theresulting solution was added 4-chloro-3-methylaniline (0.142 g, 1 mmol),then HATU (364 mg, 0.957 mmol). The reaction mixture was stirred at roomtemperature for 3 hours and left standing for 2 hours. The product wasfiltered off, washed with CH₃CN (5×), and dried at 50° C. in vacuo,resulting in compound 77 (190 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55(s, 3H), 2.32 (s, 3H), 3.92 (s, 3H), 4.13 (d, J=6.2 Hz, 2H), 4.60 (d,J=6.2 Hz, 2H), 7.31-7.40 (m, 2H), 7.54-6 7.62 (m, 2H), 7.73 (d, J=2.2Hz, 1H), 7.95 (s, 1H), 10.08 (s, 1H). Method A; Rt: 1.70 min. m/z: 396.0(M−H)⁻ Exact mass: 397.1.

Compound 78:N-(3-Chloro-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(250 mg, 0.911 mmol) and HATU (433 mg, 1.14 mmol) were dissolved in DMF(5 mL) and stirred for 10 minutes. 3-chloro-4-fluoroaniline (265 mg, 1.8mmol) and DIPEA (0.471 mL, 2.73 mmol) were added and the reactionmixture was stirred overnight at room temperature. The volatiles wereremoved under reduced pressure and the residue was purified on silicausing a heptane to EtOac gradient yielding compound 78 as a white powderafter trituration in MeOH. Method B; Rt: 0.93 min. m/z: 400.0 (M−H)⁻Exact mass: 401.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92(s, 3H), 4.13 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.34 (d, J=2.0Hz, 1H), 7.40 (t, J=9.1 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.66 (ddd,J=9.1, 4.3, 2.6 Hz, 1H), 7.96 (br. s., 1H), 8.01 (dd, J=6.9, 2.5 Hz,1H), 10.21 (s, 1H).

Compound 79:N-[4-Fluoro-3-methyl-5-(trifluoromethyl)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 79 (1.9 g) was prepared similarly as described for compound 75,using 4-fluoro-3-methyl-5-(trifluoromethyl)aniline instead of3,5-dichloro-4-fluoroaniline

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 2.31 (d, J=2.0 Hz, 3H),3.92 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.36 (d,J=2.0 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.92-8.03 (m, 3H), 10.25 (br. s,1H). Method B; Rt: 1.04 min. m/z: 448.1 (M−H)⁻ Exact mass: 449.1.Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 192.0° C.

Compound 80:N-(4-Fluoro-3,5-dimethylphenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(200 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (2 mL). HATU(0.35 g, 0.91 mmol) was added followed by diisopropylethylamine (0.38mL, 2.19 mmol). The resulting mixture was stirred for 30 minutes at roomtemperature. Then, 4-fluoro-3,5-dimethylaniline (0.2 g, 1.46 mmol) wasadded. The resulting mixture was stirred for 24 hours and next pouredonto 10 mL of ice. The mixture was extracted using 2-Me-THF (3×10 mL).The combined organics were washed with brine, dried on Na₂SO₄, filteredand concentrated in vacuo. The obtained residue was purified by silicagel column chromatography using gradient elution from heptane to EtOAc.(100:0 to 0:100). The desired fractions were concentrated in vacuo anddried in a vacuum oven at 55° C. for 24 hours yielding compound 80 (130mg): Method B; Rt: 0.93 min. m/z: 394.2 (M−H)⁻ Exact mass: 395.1.1 H NMR(400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 2.21 (d, J=1.8 Hz, 6H), 3.91 (s,3H), 4.13 (d, J=5.7 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.31 (d, J=1.8 Hz,1H), 7.43 (d, J=6.6 Hz, 2H), 7.56 (d, J=1.8 Hz, 1H), 7.94 (br. s., 1H),9.94 (br. s, 1H).

Compound 81:N-(3-Bromo-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 81 (129 mg) was prepared as described for compound 80 using3-bromo-4-fluoroaniline instead of 4-fluoro-3,5-dimethylaniline. MethodB; Rt: 0.93 min. m/z: 444.1 (M−H)⁻ Exact mass: 445.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.47-1.60 (m, 3H), 3.83-3.99 (m, 3H), 4.13 (d, J=6.4 Hz,2H), 4.60 (d, J=5.9 Hz, 2H), 7.28-7.44 (m, 2H), 7.59 (d, J=1.8 Hz, 1H),7.71 (ddd, J=9.0, 4.4, 2.4 Hz, 1H), 7.97 (br. s., 1H), 8.13 (dd, J=6.5,2.5 Hz, 1H), 10.20 (br. s., 1H).

Compound 82:1-Methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-[3-methyl-5-(trifluoro-methyl)phenyl]-1H-pyrrole-2-carboxamide

Compound 82 (167 mg) was prepared as described for compound 80 using3-methyl-5-trifluoromethylaniline instead of4-fluoro-3,5-dimethylaniline. Method B; Rt: 1.01 min. m/z: 430.2 (M−H)⁻Exact mass: 431.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 2.39(s, 3H), 3.92 (s, 3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H),7.26 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.84 (s,1H), 7.90-8.08 (m, 2H), 10.24 (br. s., 1H).

Compound 83:N-(4-Cyano-3-methylphenyl)-1-methyl-4-[(3-methyloxetan-3-ylsulfamoyl]-1H-pyrrole-2-carboxamide

Compound 83 (76 mg) was prepared as described for compound 80 using4-amino-2-methyl-benzonitrile instead of 4-fluoro-3,5-dimethylaniline.Method B; Rt: 0.81 min. m/z: 387.1 (M−H)⁻ Exact mass: 388.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.48-1.59 (m, 3H), 2.46 (s, 3H), 3.87-3.98 (m, 3H),4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.40 (d, J=2.0 6 Hz,1H), 7.62 (d, J=1.8 Hz, 1H), 7.69-7.77 (m, 2H), 7.86 (s, 1H), 7.98 (br.s., 1H), 10.32 (br. s., 1H).

Compound 84:N-(4-Chloro-3-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(200 mg, 0.729 mmol) was dissolved in DMF (5 mL) and triethylamine(0.405 mL, 2.92 mmol) and HATU (360 mg, 0.95 mmol) were added. After 10minutes, 4-chloro-3-fluoroaniline (212 mg, 1.46 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour and heatedat 50° C. for 1 hour. More 4-chloro-3-fluoroaniline (424 mg, 2.92 mmol)was added to the reaction mixture. The reaction mixture was stirred at60° C. for 1 hour. The mixture was poured into water (50 mL) andfiltered. The formed precipitate was filtered and the solid was washedwith water. The filtrate was stored for 42 hours and the formedprecipitate was filtered and washed with water. The solids werecombined, and further purified using silica gel column chromatography(ethyl acetate in heptane from 0 to 100%) resulting in compound 84 as awhite solid. The white solid was triturated in methanol (5 mL), filteredand dried in vacuum oven overnight resulting in compound 84 (119 mg) asa white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92 (s,3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.36 (d, J=1.8 Hz,1H), 7.45-7.67 (m, 3H), 7.68-8.56 (m, 2H), 10.30 (br. s., 1H). Method B;Rt: 0.96 min. m/z: 400.1 (M−H)⁻ Exact mass: 401.1.

Compound 85:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

2,4-difluoro-3-methyl-aniline (0.306 g, 2.14 mol) was dissolved inacetonitrile (50 mL, 0.957 mol),1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(0.645 g, 2.35 mmol) and Et₃N (0.891 mL, 6.41 mmol) were added. HATU(0.975 g, 2.57 mmol) was added at once. The reaction mixture was stirredat room temperature for 1 hour. Then the reaction mixture was stirred at40° C. for 80 hours. The solvent was removed, water (1×50 mL) was addedand the mixture was washed with brine (1×5 mL) and extracted with EtOAc(2×50 mL). The combined organic layers were dried with Na₂SO₄ and thesolvent was removed by evaporation. The crude mixture was purified bysilica gel chromatography (EtOAc-heptane 0/100 to 100/0). The desiredfractions were combined and evaporated. The obtained solid wascrystallized by evaporation of a acetonitrile/H₂O solution, theprecipitate was filtered off, washed with water (2 mL) and dried at 50°C. in vacuo, resulting in compound 85. Method A; Rt: 1.55 min. m/z:398.1 (M−H)⁻ Exact mass: 399.1. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.55 (s,3H), 2.18 (s, 3H), 3.89 (s, 3H), 4.13 (s, 2H), 4.59 (s, 2H), 7.07 (td,J=9.0, 1.8 Hz, 1H), 7.28-7.39 (m, 2H), 7.59 (d, J=1.8 Hz, 1H), 8.00 (br.s., 1H), 9.95 (br. s., 1H).

Compound 86:N-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 86 (127 mg) was prepared similar as described for compound 80using 4-fluoro-3-(trifluoromethoxy)aniline instead of4-fluoro-3,5-dimethylaniline. Method B, Rt: 1.01 min. m/z: 450.2 (M−H)⁻Exact mass: 451.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.92(s, 3H), 4.14 (d, J=6.2 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.35 (d, J=2.0Hz, 1H), 7.45-7.53 (m, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.68-7.77 (m, 1H),7.97 (s, 1H), 7.99-8.07 (m, 1H), 10.29 (br. s, 1H).

Compound 87:N-(3-Chloro-5-cyanophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 87 was prepared similar as described for compound 75 using3-amino-5-chlorobenzonitrile instead of 3,5-dichloro-4-fluoroaniline.The reaction mixture was filtered and the solids were washed with water.The grey powder was dissolved in ethyl acetate (300 mL) and washed withaqueous HCl (1 N, 50 mL), saturated aqueous sodium bicarbonate (30 mL)and brine, dried (Na₂SO₄), and evaporated to dryness and dried overnightin vacuum oven at 50° C., resulting in compound 87 (867 mg) as a whitepowder. Method B; Rt: 0.91 min. m/z: 407.1 (M−H)⁻ Exact mass: 408.1. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.54 (s, 3H), 3.93 (s, 3H), 4.14 (d, J=6.4Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.38 (d, J=1.8 Hz, 1H), 7.64 (d, J=1.5Hz, 1H), 7.74 (dd, J=2.0, 1.3 Hz, 1H), 8.00 (s, 1H), 8.10-8.13 (m, 1H),8.15 (t, J=2.0 Hz, 1H), 10.42 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 209.4° C.

Compound 88:N-(4-Fluoro-3-methylphenyl)-1,3,5-trimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Ethyl 1,3,5-trimethylpyrrole-2-carboxylate (1000 mg, 5.52 mmol) wasadded in 5 portions to chlorosulfonic acid (5 mL) at 0° C. undernitrogen atmosphere. The reaction mixture was warmed to room temperatureand allowed to stir overnight. The reaction mixture was slowly added toice cold water (50 mL), followed by extraction with CH₂Cl₂ (3×50 mL).The combined organic extracts were dried (Na₂SO₄) and concentratedresulting in crude ethyl4-chlorosulfonyl-1,3,5-trimethyl-pyrrole-2-carboxylate (510 mg) as brownoil which solidified on standing.

Crude ethyl 4-chlorosulfonyl-1,3,5-trimethyl-pyrrole-2-carboxylate (500mg) was dissolved in acetonitrile (50 mL) and 3-methyl-3-oxetanamine(622.9 mg, 7.15 mmol) was added. The reaction mixture was stirred atroom temperature for 2 hours. Water (100 mL) was added and the mixturewas extracted with CH₂Cl₂ (3×50 mL) and the combined organic layers werewashed with brine, dried and evaporated to afford a brown sticky oil.The oil was purified using silica gel column chromatography (ethylacetate in heptane from 0 to 100%) resulting in ethyl1,3,5-trimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(100 mg) as a white solid. Method B; Rt: 0.83 min. m/z: 329.1 (M−H)⁻Exact mass: 330.1. Ethyl1,3,5-trimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylatewas dissolved in ethanol (10 mL) and NaOH (1M in H₂O, 0.61 mL) wasadded. The resulting solution was stirred at room temperature for 42hours. The reaction mixture was stirred at 70° C. for 20 hours. NaOH (1M in H₂O, 0.61 mL) was added to the reaction mixture which was stirredat 80° C. for 64 hours. The reaction mixture was allowed to reach roomtemperature. Triethylamine hydrochloride (222 mg, 1.61 mmol) was added,the reaction mixture was evaporated to dryness and co evaporated withtoluene (2×20 mL) to afford a residue which was used as such. Theobtained residue was dissolved in DMF (5 mL). Triethylamine (0.23 mL,1.654 mmol) and HATU (150.9 mg, 0.397 mmol) were added and the reactionmixture was stirred at room temperature for 10 minutes.4-fluoro-3-methylaniline (124 mg, 0.99 mmol) was added to the reactionmixture which was stirred at room temperature for 42 hours. The reactionmixture was poured into water. The dark brown precipitate was filteredand washed with water. The filtrate was extracted with Me-THF (2×20 mL)and EtOAc (2×30 mL). The combined organic layers were washed with brine,combined with the dark brown precipitate, dried (Na₂SO₄) and evaporated.The obtained residue was purified using silica gel column chromatography(ethyl acetate in heptane from 0 to 100% and methanol in CH₂Cl₂ from 0to 2%) to afford compound 88 (17.2 mg) as a powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.49 (s, 3H), 2.23 (d, J=1.8 Hz, 3H), 2.28 (s, 3H), 2.43(s, 3H), 3.56 (s, 3H), 4.12 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H),7.10 (t, J=9.2 Hz, 1H), 7.46-7.54 (m, 1H), 7.61 (dd, J=7.0, 2.2 Hz, 1H),7.78 (br. s, 1H), 10.09 (s, 1H). Method B; Rt: 0.90 min. m/z: 408.2(M−H)⁻ Exact mass: 409.1.

Compound 89:N-(4-Fluoro-3-methylphenyl)-1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Ethyl 1,5-dimethyl-1H-pyrrole-2-carboxylate (2.5 g, 14.95 mmol) wasadded drop wise to chlorosulfonic acid (10 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was warmed to room temperature andallowed to stir overnight. The reaction mixture was slowly added to icecold water, followed by extraction with CH₂Cl₂. The combined organicextracts were dried (Na₂SO₄) and concentrated resulting in crude ethyl4-chlorosulfonyl-1,5-dimethyl-pyrrole-2-carboxylate (2.9 g) as lightpurple powder. ¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 1.32 (t, J=7.0Hz, 3H), 2.54 (s, 3H), 3.86 (s, 3H), 4.28 (q, J=7.2 Hz, 2H), 7.30 (s,1H). Crude ethyl 4-chlorosulfonyl-1,5-dimethyl-pyrrole-2-carboxylate(1500 mg, 5.65 mmol was dissolved in acetonitrile (15 mL). Hunig's base(2.4 mL, 14.1 mmol) and 3-methyl-3-oxetanamine (639 mg, 7.33 mmol) wereadded to the reaction mixture. The reaction mixture was stirred at roomtemperature for 42 hours. Water was added and the mixture was extractedwith CH₂Cl₂ (2×50 mL) and EtOAc (2×50 mL). The combined organic layerswere dried (Na₂SO₄) and evaporated to dryness. The obtained crude ethyl1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(1.8 g) was used as such. Method B; Rt: 0.77 min. m/z: 315.1 (M−H)⁻Exact mass: 316.1. Crude ethyl1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(1800 mg, 5.689 mmol) was dissolved in methanol (8 mL), LiOH (720 mg,30.1 mmol) in water (2 mL) was added and the reaction mixture was heatedat 50° C. for 2 hours. The reaction mixture was evaporated to drynessand coevaporated with toluene (2×50 mL) to afford a beige powder. Halfof the above obtained powder was dissolved in DMF (10 mL). Triethylaminehydrochloride (2349 mg, 17.1 mmol), triethylamine (1.19 mL) and HATU(1298 mg, 3.41 mmol), were added and the reaction mixture was stirred atroom temperature for 10 minutes. 4-Fluoro-3-methylaniline (712 mg, 5.688mmol), was added to the reaction mixture which was stirred at roomtemperature for 3 hours. The reaction mixture was poured into water andthe solids were filtered and washed with water to afford a beige solidwhich was purified using silica gel column chromatography (ethylacetatein heptane from 0 to 100%) to afford compound 89 as a white powder.Method B; Rt: 0.92 min. m/z: 394.1 (M−H)⁻ Exact mass: 395.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (s, 3H), 2.22 (d, J=1.6 Hz, 3H),2.43 (s, 3H), 3.83 (s, 3H), 4.11 (d, J=6.5 Hz, 2H), 4.59 (d, J=6.1 Hz,2H), 6 7.08 (t, J=9.3 Hz, 1H), 7.29 (s, 1H), 7.49-7.54 (m, 1H), 7.63(dd, J=7.3, 2.4 Hz, 1H), 7.92 (s, 1H), 9.94 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 186.6°C.

Compound 90:N-(4-Fluoro-3-methylphenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Ethyl 1,3-dimethylpyrrole-2-carboxylate (1.3 g, 7.78 mmol) was addeddrop wise to chlorosulfonic acid (5.2 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was warmed to room temperature andallowed to stir 1.5 hours. The reaction mixture was slowly added to icecold water, followed by extraction with CH₂Cl₂. The combined organicextracts were dried (Na₂SO₄) and concentrated in crude ethyl4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate (1300 mg) as a brownoil. Crude ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate(1.3 g, 4.89 mmol) was dissolved in acetonitrile (5 mL) and3-methyl-3-oxetanamine (852 mg, 9.79 mmol) was added followed by Hunig'sbase (2.11 mL, 12.23 mmol). The reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was filtered. The solidswere washed with CH₂Cl₂ and discarded. The filtrate was evaporated andthe residue was purified using silica gel column chromatography ethylacetate in heptane from 0 to 100% resulting in ethyl1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(302 mg) as sticky oil. Method B; Rt: 0.79 min. m/z: 315.1 (M−H)⁻ Exactmass: 316.1. Ethyl1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(302 mg, 0.955 mmol) was dissolved in THF (40 mL) and LiOH (114.3 mg,4.77 mmol) in water (10 mL) was added. The reaction mixture was stirredat room temperature. Methanol (20 mL) was added to the reaction mixture.The reaction mixture was stirred at room temperature overnight. MoreLiOH (5 equiv.) in water was added and the reaction mixture was heatedat 60° C. for 42 hours. The reaction mixture was evaporated to drynessand coevaporated with toluene (2×50 mL). The residue was used as such innext step. The obtained residue was dissolved in DMF (10 mL).triethylamine hydrochloride (1575 mg, 11.4 mmol), triethylamine (0.663mL, 4.7 mmol) and HATU (435 mg, 1.15 mmol) were added and the reactionmixture was stirred at room temperature for 10 minutes.4-fluoro-3-methylaniline (239 mg, 1.91 mmol) was added to the reactionmixture which was stirred at room temperature for 2 hours. The reactionmixture was stirred at 50° C. for 2 hours. Water was added to thereaction mixture and the mixture was extracted with 2-Methyl THF. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andevaporated to afford a brown oil. The oil was purified using silica gelcolumn chromatography (ethylacetate in heptane from 0 to 100%) to afforda sticky light brown oil. Compound 90 was purified using Preparative LC(Hypersyl C₁₈ BDS-3 μm, 100×4.6 mm) Mobile phase (NH₄HCO₃ 0.2% in water,methanol) the desired fractions were combined and evaporated to dryness,dissolved in methanol and evaporated to dryness. After drying in vacuocompound 90 was obtained as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.53 (s, 3H), 2.23 (d, J=1.6 Hz, 3H), 2.31 (s, 3H), 3.70 (s, 3H),4.11 (d, J=6.5 Hz, 2H), 4.61 (d, J=5.7 Hz, 2H), 6 7.11 (t, J=9.3 Hz,1H), 7.44 (s, 1H), 7.47-7.53 (m, 1H), 7.62 (dd, J=6.9, 2.4 Hz, 1H), 7.88(br. s., 1H), 10.09 (s, 1H). Method B; Rt: 0.88 min. m/z: 394.2 (M−H)⁻Exact mass: 395.1. Differential scanning calorimetry: From 30 to 300° C.at 10° C./min: peak at 160.5° C.

Compound 97:N-(4-Fluoro-3-methylphenyl)-1-methyl-4-{[(1R)-1-methyl-2-(methyl-sulfonyl)ethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.269 g, 0.813 mmol) was stirred in acetonitrile (50 mL). Et₃N(0.339 mL, 2.44 mmol) and (2R)-1-methylsulfonylpropan-2-amine (0.123 g,0.895 mmol) were added under N₂-atmosphere at room temperature. Thereaction mixture was stirred for 22 hours and next concentrated. Thecompound was precipitated from CH₂Cl₂/MeOH (4 mL, 3:1). The precipitatewas filtered off, washed with CH₂Cl₂ (2×3 mL) and dried in vacuo at 50°C., resulting in compound 97 (123 mg). Method A; Rt: 1.47 min. m/z:430.1 (M−H)⁻ Exact mass: 431.1. ¹H NMR (400 MHz, DMSO-d₆, 80° C.) 6 ppm1.20 (d, J=6.6 Hz, 3H), 2.22 (d, J=1.8 Hz, 3H), 2.94 (s, 3H), 3.10-3.17(m, 1H), 3.27-3.34 (m, 1H), 3.71-3.81 (m, 1H), 3.92 (s, 3H), 7.04 (t,J=9.2 Hz, 1H), 7.30 (d, J=1.8 Hz, 2H), 7.46-7.52 (m, 2H), 7.59 (dd,J=7.3, 2.6 Hz, 1H), 9.80 (br. s., 1H).

Compound 98:4-(tert-Butylsulfamoyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrrole-2-carboxamide

4-fluoro-3-(trifluoromethoxy)aniline (991 mg, 5.08 mmol) dissolved intoluene (10 mL) was added to4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (1.23 g, 5.079mmo) in toluene (65 mL) at reflux and refluxed 2 hours. The reactionmixture was filtered while still hot and concentrated yielding crude5-[[4-fluoro-3-(trifluoromethoxy)phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride as a beige powder which was used as such. ¹H NMR (400 MHz,acetonitrile-d₃) δ ppm 3.97 (s, 3H), 7.27-7.35 (m, 1H), 7.38 (d, J=2.0Hz, 1H), 7.57 (ddd, J=9.0, 4.0, 2.6 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H),7.87-7.94 (m, 1H), 8.79 (br. s., 1H). Tert-butylamine (342.7 mg, 4.69mmol) was added to crude5-[[4-fluoro-3-(trifluoromethoxy)phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (626 mg) in acetonitrile (52 mL) and stirred 2 hours. Water wasadded until crystallisation began. The white crystals were filtered offand dried in vacuo at 50° C. during 4 hours. Method A; Rt: 1.90 min.m/z: 436.1 (M−H)⁻ Exact mass: 437.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.17 (s, 9H), 3.91 (s, 3H), 7.12 (s, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.48(s, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.69-7.77 (m, 1H), 7.98-8.07 (m, 1H),10.28 (s, 1H).

Compound 99:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (0.426 g, 1.73mol) was dissolved in acetonitrile (40 mL). Et₃N (0.962 mL, 6.92 mmol)and 2,4-difluoro-3-methyl-aniline (0.342 g, 1.9 mmol) were added. HATU(0.789 g, 2.08 mmol) was next added at once. The reaction mixture wasstirred at room temperature for 1 hour. Then the solution was stirred at50° C. for 80 hours. The solution was allowed to cool and water (2×50mL) and brine (5 mL) were added. The solution was extracted with EtOAc(2×100 mL) and dried with Na₂SO₄. The solvent was evaporated leavingyellow oil which purified by silica gel chromatography (EtOAc-heptane0/100 to 100/0). The obtained solid was dissolved in boiling 2-propanol(1.5 mL) and water was added dropwise (1.5 mL) when still boiling. Thesolution was allowed to cool down After 90 min the white precipitate wasfiltered off, washed with 2-Propanol/water (2×1 mL) and dried at 50° C.in vacuo yielding compound 99 as white crystals. Method A; Rt: 1.72 min.m/z: 370.0 (M−H)⁻ Exact mass: 371.1. ¹H NMR (400 MHz, DMSO-d₆, 80° C.) δppm 1.06 (d, J=6.4 Hz, 6H), 2.18 (t, J=1.9 Hz, 3H), 3.33 (dt, J=13.0,6.6 Hz, 1H), 3.89 (s, 3H), 6.85 (br. s., 1H), 7.00 (td, J=8.9, 1.8 Hz,1H), 7.25 (s, 1H), 7.37 (m, J=8.8, 8.8, 6.2 Hz, 1H), 7.43 (d, J=1.8 Hz,1H), 9.62 (br. s., 1H)

Synthesis of1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid

Methyl 4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5 g, 21.04 mmol)was dissolved in acetonitrile (50 mL). To this was addeddiisopropylethylamine (9.06 mL, 52.6 mmol) followed by(S)-1,1,1-trifluoro-2-propylamine (3.57 g, 31.6 mmol) and the resultingmixture was refluxed overnight. Then the mixture was cooled to roomtemperature and concentrated in vacuo. The resulting residue wasdissolved in dichloromethane (250 mL) and this was washed with HCl(2×150 mL). The organics were dried on sodium sulphate, filtered andconcentrated in vacuo yielding crude methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(6.6 g) which was used as such. Methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(6.6 g, 19.7 mmol) was dissolved in tetrahydrofuran (56 mL). To this wasadded lithium hydroxide (1.655 g, 69.1 mmol) in distilled water (7.5 mL)followed by methanol (3 mL). The resulting mixture was stirredovernight. The mixture was concentrated until only water remained andextra distilled water (15 mL) was added. The mixture was neutralisedwith hydrochloric acid (1M, aq). The resulting mixture was extractedusing 2-methyltetrahydrofuran (3×20 mL). The combined extracts weredried on sodium sulphate, filtered and concentrated in vacuo yielding1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (5.34 g).

Compound 100 to 105 were prepared similarly as described for compound80, using1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid instead of1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid andthe corresponding aniline instead of 4-fluoro-3,5-dimethylaniline. Afteraddition of the aniline, the mixture was stirred at 50° C. for 6 hoursinstead of 24 hours at room temperature.

Compound 100:N-(3-Bromo-4,5-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 100 was purified by silica gel chromatographyheptane-EtOAc 100/0 to 0/100. The product was crystallized fromdiisopropylether (15 mL)/iPrOH (3.5 mL). The product was filtered off,washed with diisopropylether (3×), and dried at 50° C. in vacuo,resulting in compound 100 (251 mg). Method A; Rt: 1.98 min. m/z: 489.8(M−H)⁻ Exact mass: 491.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.8Hz, 3H), 3.84-4.00 (m, 4H), 7.36 (d, J=2.0 Hz, 1H), 7.66 (d, J=1.8 Hz,1H), 7.80-7.93 (m, 2H), 8.20 (br. s., 1H), 10.31 (br. s., 1H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ ppm −138.51-−138.34 (m, 1F), −133.99-−133.81 (m,1F), −76.07 (d, J=7.9 Hz, 3F). Differential scanning calorimetry: From30 to 300° C. at 10° C./min: peak at 199.0° C.

Compound 101:N-(3-Bromo-4-fluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 101 was stirred in CH₂Cl₂ (5 mL), filtered off, andwashed with CH₂Cl₂ (1×). The product (0.289 g) was crystallized fromiPrOH—H₂O 3/1 (6 mL), filtered off, washed with iPrOH—H₂O 3/1 (3×), anddried at 50° C. in vacuo, resulting in compound 101 (70 mg). Method B;Rt: 1.07 min. m/z: 470.0 (M−H)⁻ Exact mass: 471.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H), 3.88-3.96 (m, 4H), 7.33-7.41 (m,2H), 7.63 (d, J=1.5 Hz, 1H), 7.71 (ddd, J=9.0, 4.4, 2.6 Hz, 1H),8.11-8.28 (m, 2H), 10.21 (s, 1H).

Compound 102:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 102 was stirred in CH₂Cl₂ (5 m), filtered off, and washedwith CH₂Cl₂ (2×). The product was crystallized from iPrOH (12.5 mL)+H₂O(2.5 m), filtered off, washed with iPrOH—H₂O 4/1 (2×) and iPrOH, anddried at 50° C. in vacuo, resulting in compound 102 (93 mg). Method B;Rt: 0.97 min. m/z: 417.1 (M−H)⁻ Exact mass: 418.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.07 (d, J=7.0 Hz, 3H), 3.84-3.99 (m, 4H), 7.36 (d, J=2.0Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.64 (br. s., 1H), 7.97-8.04 (m, 1H),8.22 (dd+br. s., J=5.7, 2.6 Hz, 2H), 10.38 (br. s., 1H).

Alternative Synthesis of Compound 102:

Methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(5 g, 15.9 mmol) was dissolved in of dry tetrahydrofuran (50 m) under ablanket of nitrogen. 5-amino-2-fluorobenzonitrile (2.82 g, 20.68 mmol)was added and the mixture was cooled in an ice-water bath while stirringunder nitrogen. Lithium bis(trimethylsilyl)amide (1M in toluene, 47.73m, 47.73 mmol) was added drop wise over a period of 10 minutes. Theresulting mixture was stirred for 1 hour while cooling was continued.

An extra 2 equivalents of lithium bis(trimethylsilyl)amide (1M intoluene, 31.82 m, 31.82 mmol) were added drop wise over a period of 10minutes. The resulting mixture was stirred for 1 hour while cooling wascontinued. An extra equivalent of lithium bis(trimethylsilyl)amide (1Min toluene, 15.9 m, 15.9 mmol) was added drop wise over a period of 5minutes. Next, the mixture was quenched with saturated ammonium chloride(150 mL/aq) and the resulting mixture was extracted using EtOAc (3×150mL). The combined extracts were washed with brine (200 mL), dried onNa₂SO₄, filtered and concentrated in vacuo. The obtained residue wasdissolved in dichloromethane (10 mL) and this was loaded on a dry silicaplug (330 g). This was purified by column chromatography using gradientelution from heptane to EtOAc. (100:0 to 0:100). The desired fractionswere collected and concentrated in vacuo yielding a slightly red powder.This powder was recrystallized out of MeOH/water. The obtained crystalswere collected on a filter, rinsed with water and diisopropylether anddried in a vacuum oven at 55° C. for 24 hours yielding compound 102(3.92 g) as a bright white powder. [α]₅₈₉ ²⁰=+2.7° (c 0.96 w/v %, MeOH).[α]₅₈₉ ²⁰=+21.8° (c 0.37 w/v %, DMF). Differential scanning calorimetry:From 30 to 300° C. at 10° C./min: peak at 213.4° C. SFC analysis: AD-H250 mm×4.6 mm, Flow: 5 mL/min Mobile phase: 10-55% MeOH (containing 0.2%iPrNH₂) @ 14.5% rate, down to 50% and hold for 2.55 min @ 50%,Temperature: 40° C.: Compound 102 (first eluding), containing nodetectable compound 157 (second eluding). ¹H NMR (600 MHz, DMSO-d₆) δppm 1.08 (d, J=7.0 Hz, 3H), 3.88-3.97 (m, 1H), 3.93 (s, 3H), 7.37 (d,J=1.9 Hz, 1H), 7.53 (t, J=9.2 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 8.01(ddd, J=9.2, 4.8, 2.7 Hz, 1H), 8.19 (br. s., 1H), 8.22 (dd, J=5.8, 2.7Hz, 1H), 10.39 (br. s., 1H).

Compound 103:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 103 was triturated from refluxing CH₂Cl₂ (10 mL). Thesuspension was cooled to room temperature, the solids were filtered andwashed with CH₂Cl₂ (2 mL) resulting in compound 103 (308 mg) as whitesolid after drying in vacuo at 50° C. Method B; Rt: 1.13 min. m/z: 444.0(M−H)⁻ Exact mass: 445.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.8Hz, 3H), 3.85-3.98 (m, 4H), 7.36 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.3 Hz,1H), 7.75-7.87 (m, 2H), 8.19 (br. s, 1H), 10.33 (br. s., 1H).

Compound 104:N-(3,4-Difluoro-5-methylphenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 104 was triturated from refluxing CH₂Cl₂ (10 mL). Thesuspension was cooled to room temperature, the solids were filtered andwashed with CH₂Cl₂ (2 mL) resulting in compound 104 (481 mg) as whitesolid after drying in vacuo at 50° C. Method B; Rt: 1.08 min. m/z: 424.0(M−H)⁻ Exact mass: 425.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=7.0Hz, 3H), 2.28 (d, J=2.0 Hz, 3H), 3.86-3.98 (m, 4H), 7.34 (d, J=2.0 Hz,1H), 7.38-7.44 (m, 1H), 7.62 (d, J=1.3 Hz, 1H), 7.66 (ddd, J=12.9, 7.1,2.4 Hz, 1H), 8.16 (br. s., 1H), 10.15 (s, 1H).

Compound 105:N-(3-Chloro-4-fluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Crude compound 105 was triturated from refluxing CH₂Cl₂ (10 mL). Thesuspension was cooled to room temperature, the solids were filtered andwashed with CH₂Cl₂ (2 mL). The obtained solid was triturated with warmacetonitrile, the mixture was cooled to room temperature. The solidswere filtered and to the obtained filtrate, water (3 mL) was added toform a white solid which was filtered and washed with water, resultingin compound 105 as white powder. Method B; Rt: 1.08 min. m/z: 426.0(M−H)⁻ Exact mass: 427.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=7.0Hz, 3H), 3.87-3.98 (m, 4H), 7.35 (d, J=2.0 Hz, 1H), 7.40 (t, J=9.1 Hz,1H), 7.60-7.70 (m, 2H), 8.01 (dd, J=6.9, 2.5 Hz, 1H), 8.16 (br. s., 1H),10.23 (s, 1H).

Compound 94:3-Fluoro-N-(4-fluoro-3-methylphenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

A solution of Et₃N (0.179 mL, 1.29 mmol) in DMF (1.9 mL) was added to3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid (125 mg, 0.428 mmol), HATU (204 mg, 0.535 mmol),4-fluoro-3-methylaniline (107 mg, 0.857 mmol) and stirred overnight. Thesolution was subjected to column chromatography using a gradient from 10till 100% EtOAc in heptane. The product fractions were combined andconcentrated. Compound 94 (78 mg) was obtained as a white powder afterdrying in vacuo at 50° C. Method A; Rt: 1.66 min. m/z: 397.9 (M−H)⁻Exact mass: 399.1._¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 2.23(d, J=1.5 Hz, 3H), 3.79 (s, 3H), 4.17 (d, J=6.4 Hz, 2H), 4.65 (d, J=6.2Hz, 2H), 7.10 (t, J=9.2 Hz, 1H), 7.43-7.51 (m, 2H), 7.59 (dd, J=7.0, 2.4Hz, 1H), 8.28 (s, 1H), 10.01 (s, 1H).

Compound 106:N-(3-Bromo-4-fluorophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 106 (131 mg) was prepared similarly as described for compound94, using 3-bromo-4-fluoroaniline instead of 4-fluoro-3-methylaniline.Method A; Rt: 1.73 min. m/z: 463.8 (M−H)⁻ Exact mass: 465.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.80 (s, 3H), 4.17 (d, J=6.4 Hz, 2H),4.64 (d, J=5.9 Hz, 2H), 7.37 (t, J=8.8 Hz, 1H), 7.51 (d, J=4.4 Hz, 1H),7.64 (ddd, J=9.0, 4.4, 2.6 Hz, 1H), 8.08 (dd, J=6.4, 2.6 Hz, 1H), 8.30(s, 1H), 10.20 (s, 1H).

Compound 107:N-[3-(Difluoromethyl)-4-fluorophenyl]-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 107 (149 mg) was prepared similarly as described for compound94, using 3-(difluoromethyl)-4-fluoro-aniline instead of4-fluoro-3-methylaniline. Method A; Rt: 1.63 min. m/z: 334.0 (M−H)⁻Exact mass: 435.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.80(s, 3H), 4.18 (d, J=6.6 Hz, 2H), 4.65 (d, J=5.9 Hz, 2H), 7.04-7.43 (m,2H), 7.51 (d, J=4.6 Hz, 1H), 7.76-7.86 (m, 1H), 8.01 (dd, J=6.3, 2.5 Hz,1H), 8.30 (s, 1H), 10.26 (s, 1H).

Compound 108:N-(3-Chloro-4-fluorophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 108 (149 mg) was prepared similarly as described for compound94, using 3-chloro-4-fluoroaniline instead of 4-fluoro-3-methylaniline.Method A; Rt: 1.70 min. m/z: 417.9 (M−H)⁻ Exact mass: 419.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.80 (s, 3H), 4.17 (d, J=6.4 Hz, 2H),4.64 (d, J=6.2 Hz, 2H), 7.41 (t, J=9.1 Hz, 1H), 7.51 (d, J=4.4 Hz, 1H),7.60 (ddd, J=9.1, 4.3, 2.6 Hz, 1H), 7.96 (dd, J=6.8, 2.4 Hz, 1H), 8.30(s, 1H), 10.22 (s, 1H).

Compound 109:3-Fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-N-(2,4,5-trifluorophenyl)-1H-pyrrole-2-carboxamide

Compound 109 (35 mg) was prepared similarly as described for compound94, using 2,4,5-trifluoroaniline instead of 4-fluoro-3-methylaniline.After overnight stirring at room temperature, the mixture was stirred at60° C. for 3 hours. Method A; Rt: 1.56 min. m/z: 420.1 (M−H)⁻ Exactmass: 421.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.81 (s, 3H),4.17 (d, J=6.4 Hz, 2H), 4.64 (d, J=5.9 Hz, 2H), 7.53 (d, J=4.6 Hz, 1H),7.67 (td, J=10.6, 7.3 Hz, 1H), 7.80-7.90 (m, 1H), 8.32 (s, 1H), 9.79 (s,1H).

Compound 110:N-(2,4-Difluoro-3-methylphenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 110 (90 mg) was prepared similarly as described for compound94, using 2,4-difluoro-3-methyl-aniline instead of4-fluoro-3-methylaniline. Method A; Rt: 1.68 min. m/z: 415.9 (M−H)⁻Exact mass: 417.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3H),2.15-2.22 (m, 3H), 3.80 (s, 3H), 4.17 (d, J=6.4 Hz, 2H), 4.65 (d, J=6.2Hz, 2H), 7.06 (td, J=9.0, 1.5 Hz, 1H), 7.46-7.56 (m, 2H), 8.30 (s, 1H),9.63 (s, 1H).

Compound 111:N-(3-Chloro-4,5-difluorophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 111 (46 mg) was prepared similarly as described for compound94, using 3-chloro-4,5-difluoro-aniline instead of4-fluoro-3-methylaniline. The mixture was stirred at 65° C. overnightinstead of room temperature. Method A; Rt: 1.80 min. m/z: 435.9 (M−H)⁻Exact mass: 437.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.80(s, 3H), 4.17 (d, J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.54 (d, J=4.4Hz, 1H), 7.70-7.80 (m, 2H), 8.32 (s, 1H), 10.30 (s, 1H).

Compound 112:4-(tert-butylsulfamoyl)-N-(2,4-difluoro-3-methyl-phenyl)-1-methyl-pyrrole-2-carboxamide

5-[(2,4-difluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (prepared similarly as described for5-[(3,4-difluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride,using 2,4-difluoro-3-methyl-aniline instead of 3,4-difluoroaniline; 0.25g, 0.72 mmol) was stirred in acetonitrile (20 mL). DIPEA (0.494 mL, 2.87mmol) and tert-butylamine (0.152 mL, 1.43 mmol) were added underN₂-atmosphere at room temperature. The reaction mixture was stirred in asealed tube at 80° C. for 5 hours and further at room temperature formore than 80 hours. The solvent was evaporated and the residue wasdissolved in (CH₂Cl₂/MeOH (5 mL, 90:10) and purified by silica gelchromatography [EtOAc-heptane 0/100 to 100/0] and further purified byreverse phase column chromatography. The resulting solid was trituratedfrom Heptane/diisopropyl ether (4:1, 2.5 mL). The formed suspension wasfiltered. The filtercake was washed with heptane/diisopropylether (4:1,5 mL) and dried at 50° C. in vacuo yielding compound 112 (120 mg) as awhite solid. Method A; Rt: 1.71 min. m/z: 384.1 (M−H)⁻ Exact mass:385.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H), 2.18 (s, 3H), 3.88(s, 3H), 7.05 (td, J=8.9, 1.5 Hz, 1H), 7.12 (s, 1H), 7.29 (s, 1H), 7.34(td, J=8.7, 6.3 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 9.89 (s, 1H).

Compound 113:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

Compound 113 (43 mg) was prepared similarly as described for compound94, using 5-amino-2-fluoro-benzonitrile instead of4-fluoro-3-methylaniline but stirred 24 hours at 65° C. and 48 hours at100° C. The residue after column was crystallized from acetonitrile (10mL) upon addition of water. The crystals were dried overnight at 50° C.in vacuo. Method A; Rt: 1.44 min. m/z: 409.0 (M−H)⁻ Exact mass: 410.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.80 (s, 3H), 4.18 (d,J=6.4 Hz, 2H), 4.64 (d, J=5.9 Hz, 2H), 7.48-7.58 (m, 2H), 7.96 (ddd,J=9.2, 4.8, 2.6 Hz, 1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H), 8.32 (s, 1H),10.34 (s, 1H).

Compound 114:4-[(1-Carbamoylcyclopropyl)sulfamoyl]-N-(3-chloro-4,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Methyl 1-aminocyclopropanecarboxylate (1.016 g, 6.7 mmol) was dissolvedin dry dichloromethane (50 ml) and dry DIPEA (3.08 ml) under N₂-atm.5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (prepared similarly as described for compound 57, 1.65 g, 4.47mmol) was added. The reaction mixture was stirred at room temperaturefor 3 h. Dry DMF (1 mL) was added and the reaction mixture was stirredfor 22 h. Then the mixture was washed with HCl 1M (50 mL). The layerswere separated, precipitate 1 was filtered off and washed with CH₂Cl₂(10 mL). The organic layer was dried with Na₂SO₄ and the filtrate wasevaporated resulting in residue 1. The water layer was extracted withEtOAc (100 mL). The layers were separated and the organic layer wasdried with Na₂SO₄ and the filtrate was evaporated resulting in residue2. Residue 1, 2 and precipitate 1 were combined giving methyl1-[[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]sulfonylamino]-cyclopropanecarboxylate(2.0 g) This material was dissolved in methanol (20 mL) and NaOH 1M(13.4 mL, 13.4 mmol) was added. The reaction mixture was stirred for 20h. After 8 h, THF (6 mL) was added and the mixture was stirred furtherfor 18 h. Then the mixture was successively stirred at 50° C. for 9 h,room temperature for 80 h, 50° C. for 8 h and 18 h at room temperature.The methanol/THF was distilled off and the mixture was extracted withEt₂O. The layers were separated and HCl 1M (14 mL) was added to thewater layer. The water layer was extracted with MeTHF. The organic layerwas evaporated resulting in1-[[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]sulfonylamino]cyclopropanecarboxylicacid as a yellow residue (1164 mg) which was used as such. This material(700 mg, 16.1 mmol) was stirred in CH₃CN (50 mL), CDI (654 mg, 40.3mmol) was added and the resulting solution was stirred at roomtemperature in a sealed tube for 2.5 h [white precipitation wasobserved]. Then, NH₃ (0.4 M in THF, 80.7 mL, 32.3 mmol) was added atonce. The mixture was stirred at room temperature for more than 80 h.The solvent was evaporated and the yellow residue was dissolved in EtOAc(80 mL). The solution was washed with HCl 1M (50 mL) and saturated NaClsolution (5 mL). The layers were separated and the organic was driedwith Na₂SO₄. The solvent was evaporated and the beige residue wasstirred in warm CH₃CN. The suspension was filtered off leaving a whitefiltercake. The filtercake was washed with CH₃CN and dried in vacuo at50° C., resulting in compound 114 (319 mg) Method A; Rt: 1.56 min. m/z:431.0 (M−H)⁻ Exact mass: 432.05. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.94-0.99 (m, 2H), 1.10-1.18 (m, 2H), 3.91 (s, 3H), 6.87 (br. s., 1H),7.21 (br. s., 1H), 7.32 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H),7.76-7.87 (m, 2H), 8.20 (br. s., 1H), 10.29 (br. s., 1H).

Compound 115:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-{[1-(methylcarbamoyl)cyclopropyl]sulfamoyl}-1H-pyrrole-2-carboxamide

1-[[5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrol-3-yl]sulfonylamino]-cyclopropanecarboxylicacid (364 mg, 0.839 mmol) was stirred in dry CH₃CN (30 mL). Afteraddition of CDI (340 mg, 2.1 mmol) the mixture became a solution. Thereaction mixture was stirred at room temperature in a sealed tube for2.5 h. Then Methylamine (2 M in THF, 12 mL, 24 mmol) was added at once.The mixture was stirred at room temperature for 2 h. The reaction wasstirred during 80 h. The solvent was distilled off and the residuedissolved in 5 mL CH₂Cl₂/MeOH (90:10) and purified by flashchromatography on silica using a gradient EtOAc-heptane 0/100 to 100/0.The desired fractions were combined and the solvent was evaporated,resulting in compound 115 (199 mg) Method A; Rt: 1.60 min. m/z: 445.0(M−H)⁻ 447.0 (M+H)⁺ Exact mass: 446.10. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.91-0.98 (m, 2H), 1.08-1.15 (m, 2H), 2.55 (d, J=4.6 Hz, 3H), 3.91 (s,3H), 7.31 (d, J=2.0 Hz, 1H), 7.41 (d, J=4.6 Hz, 1H), 7.58 (d, J=1.5 Hz,1H), 7.76-7.86 (m, 2H), 8.14 (br. s., 1H), 10.31 (br. s., 1H).

Compound 116:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(2,4-difluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (310 mg, 0.89 mmol) prepared similarly as described in thesynthesis for compound 57 using 2,4-difluoro-3-methyl-aniline (251 mg,2.22 mmol) was stirred in dry CH₃CN (25 mL).(2R)-1,1,1-trifluoropropan-2-amine (251 mg, 2.22 mmol) was added underN₂-atm at room temperature.

The mixture was stirred in a sealed tube at 75° C. for 42 hours. Thenthe reaction mixture was concentrated, water was added (8 mL) and theformed precipitate was filtered off and washed with water/CH₃CN (10 mL5:1). The obtained red solid was suspended in boiling diisopropyl ether(3 mL) and 2-propanol (2 mL) was added dropwise. The mixture was leftstanding for 90 min and then filtered. The precipitate was washed withdiisopropyl ether/2-propanol (4:1, 6 mL) and dried in vacuo at 50° C.yielding compound 116 as a slightly red-purple solid (240 mg) Method A;Rt: 1.71 min. m/z: 424.0 (M−H)⁻ 426.0 (M+H)⁺ Exact mass: 425.08. ¹H NMR(360 MHz, DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H), 2.18 (s, 3H), 3.87-3.97(m, 4H), 7.07 (td, J=9.0, 1.5 Hz, 1H), 7.31-7.39 (m, 2H), 7.64 (d, J=1.8Hz, 1H), 8.18 (br. s., 1H), 9.95 (s, 1H) Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 206.64° C.

Compound 117:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-{[1-(trifluoromethyl)-cyclopropyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(2,4-difluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (310 mg, 0.89 mmol) was stirred in dry acetonitrile (25 mL) anddry DIPEA (0.61 mL, 3.56 mmol). 1-(trifluoromethyl)cyclopropanamine (222mg, 1.78 mmol) was added under N₂-atm at room temperature. The reactionmixture was stirred in a sealed tube at 75° C. for 24 h and 110 h at 95°C. Then 1 eq of 1-(trifluoromethyl)cyclopropanamine was added and themixture was stirred at 95° for 24 h. The solvent was evaporated leavingyellow oil which was dissolved in CH₂Cl₂/Methanol (80/20; 5 mL) andpurified by Flash Chromatography [Biotage Isolera 1//GraceResolve Silica12 g//EtOAc-heptane 0/100 to 100/0]. The desired fractions were combinedand the solvent was evaporated leaving a red colored solid, which wasdissolved in a boiling mixture of 2 mL of diisopropyl ether and 3 mL ofCH₃CN. The solution was allowed to cool while stirring. After 45 min theformed precipitate was filtered off and was washed once with its ownfiltrate and at the end with 2 mL of diisopropyl ether. The white solidwas dried in vacuo at 50° C. Method B; Rt: 1.01 min. m/z: 436.0 (M−H)⁻Exact mass: 437.08. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.08-1.22 (m, 4H),2.18 (s, 3H), 3.88 (s, 3H), 7.07 (td, J=9.0, 1.5 Hz, 1H), 7.27 (d, J=1.8Hz, 1H), 7.34 (td, J=8.8, 6 6.2 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 8.76(br. s., 1H), 9.95 (s, 1H).

Compound 118:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

The compound was prepared similarly as compound 117 using 2.5 eq of1,1,1-trifluoro-2-methyl-propan-2-amine instead of1-(trifluoromethyl)cyclopropanamine. The reaction mixture was stirred ina sealed tube at 75° C. for 18 h and for 80 h at 95° C. Method B; Rt:1.01 min. m/z: 438.0 (M−H)⁻ Exact mass: 439.10. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.37 (s, 6H), 2.19 (s, 3H), 3.90 (s, 3H), 7.06 (td,J=9.0, 1.4 Hz, 1H), 7.28-7.39 (m, 2H), 7.56 (d, J=1.8 Hz, 1H), 6 8.05(br. s., 1H), 9.94 (s, 1H) Differential scanning calorimetry: From 30 to300° C. at 10° C./min: peak at 164.23° C.

Compound 119:N-(2,4-Difluoro-3-methylphenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

The compound was prepared similarly as compound 117 using(2S)-1,1,1-trifluoropropan-2-amine instead of1-(trifluoromethyl)cyclopropanamine, the reaction mixture was stirred ina sealed tube for 42 h at 95° C. Then the reaction mixture wasconcentrated and water was added (8 mL) and the formed precipitate wasfiltered off and dried in vacuo at 50° C. yielding compound 119 as apowder. Method A; Rt: 1.71 min. m/z: 424.0 (M−H)⁻ Exact mass: 425.08. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J=7.0 Hz, 3H), 2.18 (s, 3H),3.87-3.98 (m, 4H), 7.06 (td, J=8.9, 1.5 Hz, 1H), 7.30-7.40 (m, 2H), 7.63(d, J=1.8 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 9.92 (s, 1H) Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 207.52.

Compound 120:N-(3-Chloro-2,4-difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(3-chloro-2,4-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (900 mg, 2.44 mmol) prepared similarly as in the synthesis forcompound 57 using 3-chloro-2,4-difluoro-aniline (3.5 g, 14.46 mmol) wasstirred in dry CH₃CN (10 mL). (2R)-1,1,1-trifluoropropan-2-amine (689mg, 6.1 mmol) was added under N₂-atm at room temperature. The reactionmixture was stirred in a sealed tube at 85° C. for 6 h and left standingfor 18 h. The solvent was evaporated and the red residue was suspendedin DCM. The formed precipitate was filtered off and dried under vacuumat 50° C. The filtrate was concentrated till precipitation took place.The formed precipitate was filtered off. The combined precipitates wererecrystallized in DIPE/ACN (1:1; 6 mL), left stirring for 2 h then leftstanding for 18 h, filtered off and dried under vacuum at 50° C. Thefiltrate was left standing for 18 h. The formed precipitate was filteredoff and dried under vacuum at 50° C. The obtained white solid wasrecrystallized in DIPE/ACN (1:1; 4 mL), left stirring for 2 h then leftstanding for 18 h, filtered off and dried under vacuum at 50° C. The 2solids were combined (394 mg). Method A; Rt: 1.85 min. m/z: 444.0 (M−H)⁻Exact mass: 445.03. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, J=7.0 Hz,3H), 3.85-4.00 (m, 4H), 7.30-7.41 (m, 2H), 7.53 (td, J=8.7, 5.8 Hz, 1H),7.65 (d, J=1.5 Hz, 1H), 7.97 (br. s., 1H), 10.14 (br. s., 1H).

Alternative Synthesis of Compound 120:

Methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(6.61 g, 21.03 mmol) and 3-chloro-2,4-difluoroaniline (4.13 g, 25.2mmol) were dissolved in tetrahydrofuran (150 mL) and this was stirredand cooled in an ice-water bath. Over a period of 5 minutes lithiumbis(trimethylsilyl)amide in toluene (63.1 mL, 1 M, 63.1 mmol) was addeddropwise. The resulting mixture was stirred for 1 h while cooling wascontinued. Another 2 eq of lithium bis(trimethylsilyl)amide in toluene(42.1 mL, 1 M, 42.1 mmol) were added and the resulting mixture wasstirred for 1 hour at room temperature. The resulting mixture wasquenched using ammonium chloride (sat./200 mL). The resulting mixturewas extracted using EtOAc (3×250 mL). The combined extracts were washedwith brine (250 mL), dried on Na₂SO₄, filtered and concentrated in vacuoyielding a brown powder. This powder was crystallized twice out ofmethanol/water. The precipitation was collected on a glass filter. Theobtained powder was purified by silica gel column chromatography usinggradient elution from heptane to EtOAc (100:0 to 0:100). The obtainedresidue was crystallized again out of methanol/water. The white crystalswere collected on a glass filter and dried in a vacuum oven at 55° C.for 24 hours yielding compound 120 (3.03 g) as a white powder.Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 217.6° C.

Compound 121:N-(3-Chloro-2,4-difluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

5-[(3-chloro-2,4-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (900 mg, 2.44 mmol) prepared similarly as in the synthesis forcompound 57 3-chloro-2,4-difluoro-aniline (3.5 g, 14.46 mmol) wasstirred in dry CH₃CN (10 mL). 3-methyloxetan-3-amine (255 mg, 2.93 mmol)was added under N₂-atm. The reaction mixture was stirred in a sealedtube at room temperature for 18 h. The solvent was evaporated. Theresidue was stirred in CH₂Cl₂. The formed precipitate was filtered off[fraction 1]. The filtrate was evaporated and the residue was dissolvedin CH₂Cl₂/MeOH (9/1, 5 mL) and purified by Flash Chromatography [BiotageIsolera 1//GraceResolve Silica 12 g//EtOAc-heptane 0/100 to 100/0]. Thedesired fractions were combined and the solvent was evaporated leaving awhite solid which was recrystallized in diisopropyl ether/CH₃CN (1:1; 6mL), left stirring for 2 h then left standing for 18 h, filtered off anddried in vacuo at 50° C. yielding white powder which was combined withfraction 1. Method B; Rt: 0.88 min. m/z: 418.0 (M−H)⁻ Exact mass:419.05. 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 3.89 (s, 3H), 4.14(d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.31-7.38 (m, 2H), 7.53 (td,J=8.7, 5.8 6 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.98 (br. s., 1H), 10.14(br. s., 1H).

Synthesis of methyl 4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate

Chlorosulfonic acid (200 mL, 3.01 mol) was cooled to 0° C. and to thisstirring liquid was added methyl 1-methylpyrrole-2-carboxylate (75 g,538.97 mmol) drop wise. After addition the mixture was allowed to reachroom temperature. Then it was stirred for another hour. The resultingmixture was added drop wise to a mechanically stirred, temperaturecontrolled ice-water mixture (2500 mL) keeping the temperature under 5°C. A white precipitation was formed. This precipitate was collected on aglass filter and this was washed with cold water (1000 mL). The obtainedwhite powder was dried in a vacuum oven at 55° C. for 24 hours yieldingmethyl 4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (99 g) as abright white powder.

Synthesis of Methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

Methyl 4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (15 g, 63.11mmol) was loaded in a pressure tube and this was dissolved inacetonitrile (150 mL). To this solution was added diisopropylethylamine(27.2 mL, 157.8 mmol) followed by (R)-1,1,1-trifluoro-2-propylamine(10.7 g, 94.7 mmol). The pressure tube was flushed with nitrogen andclosed. Then it was stirred in a pre-heated oil bath at 80° C. for 6hours. The mixture was cooled to room temperature and concentrated invacuo. The residue was dissolved in dichloromethane (500 mL) and thiswas washed with HCl (1M/aq/2×250 mL). The organics were dried on Na₂SO₄,filtered and concentrated in vacuo. The obtained residue was dried in avacuum oven at 55° C. for 24 hours yielding methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylateas a yellowish powder (18 g).

Compound 122:1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-[3-(trifluoromethyl)phenyl]pyrrole-2-carboxamide

Into a 100 mL round bottom flask equipped with a magnetic stir bar wasplaced methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1 g, 3.18 mmol), anhydrous THF (40 mL), and 3-aminobenzotrifluoride(666 mg, 4.14 mmol). The vial was sealed and placed into an ice-waterbath and to it was added LHMDS (9.6 mL of a 1 M solution in THF) slowlyvia syringe (approx rate of 2 mL/min). Conversion to product seen after30 min at 0° C. Sat. aq. ammonium chloride was added to quench thereaction. This was diluted with ethyl acetate (100 mL) and the mixturepartitioned with ethyl acetate (3×100 mL). The organic layers werecombined, dried (magnesium sulfate), the solids were removed byfiltration and the solvents of the filtrate were removed under reducedpressure. The crude was partially purified via silica columnchromatography using a dichloromethane to ethylacetate gradient. Thesolvent of the best fractions were removed under reduced pressure andthe crude was recrystallized in ethanol/water. (1228 mg) Method B; Rt:1.92 min. m/z: 442.0 (M−H)⁻ Exact mass: 443.10. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H), 3.86-3.92 (m, 1H), 3.94 (s, 3H),7.33-7.47 (m, 2H), 7.58 (t, J=8.0 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.99(d, J=8.8 Hz, 1H), 8.11-8.24 (m, 2H), 10.34 (s, 1H).

Compound 123:N-(3-Chloro-4-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Into a 100 mL round bottom flask, equipped with a magnetic stir bars wasplaced methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1 g, 3.18 mmol), anhydrous THF (40 mL), and 3-chloro-4-fluoro-aniline(602.1 mg, 4.136 mmol). The flask was sealed and placed into anice-water bath and to it was added LHMDS (9.6 mL of a 1M solution inTHF/ethylbenzene) slowly via syringe (approx rate of 2 mL/min).Conversion to product seen after 30 min at 0° C. Sat. aq. ammoniumchloride was added to quench the reaction. This was diluted with ethylacetate (100 mL) and the mixture partitioned with ethyl acetate (3×100mL). The organic layers were combined, dried (magnesium sulfate), thesolids were removed by filtration and the solvents of the filtrate wereremoved under reduced pressure. The crudes were partially purified viasilica column chromatography using a dichloromethane to ethylacetategradient. The solvent of the best fractions were removed under reducedpressure. The residue was recrystallized from iPrOH (772 mg) Method A;Rt: 1.79 min. m/z: 426.0 (M−H)⁻ Exact mass: 427.04. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (d, J=7.0 Hz, 3H), 3.85-4.01 (m, 1H), 3.94 (s, 3H),7.38 (d, J=2.0 Hz, 1H), 7.51 (t, J=9.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H),7.99-8.09 (m, 1H), 8.14-8.24 (m, 2H), 10.36 (s, 1H).

Compound 124:N-(3-Bromo-4-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 124 (598 mg) was prepared similarly as described for compound123, using 3-bromo-4-fluoro-aniline instead of3-chloro-4-fluoro-aniline. Method B; Rt: 1.07 min. m/z: 472.0 (M−H)⁻ 960(2M+18) Exact mass: 471.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d,J=7.0 Hz, 3H), 3.84-3.99 (m, 1H), 3.92 (s, 3H), 7.32-7.41 (m, 2H), 7.64(d, J=1.8 Hz, 1H), 7.70 (ddd, 6 J=9.0, 4.4, 2.6 Hz, 1H), 8.11-8.20 (m,2H), 10.21 (s, 1H).

Compound 125:N-[4-Fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 125 (664 mg) was prepared similarly as compound 123 using4-fluoro-3-(trifluoromethyl)aniline (740.9 mg, 4.136 mmol)3-chloro-4-fluoro-aniline. Method B; Rt: 1.96 min. m/z: 460.0 (M−H)⁻479.2 (M+18) Exact mass: 461.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08(d, J=7.04 Hz, 3H) 3.87-3.98 (m, 1H) 3.93 (s, 3H) 7.40 (t, J=9.13 Hz,1H) 7.38 (d, J=1.76 Hz, 1H) 7.65 (d, J=1.76 Hz, 1H) 7.68 (ddd, J=9.02,4.40, 2.64 Hz, 1H) 8.03 (dd, J=6.82, 2.64 Hz, 1H) 8.17 (d, J=8.80 Hz,1H) 10.28 (s, 1H).

Compound 126:N-(3-Cyano-4-fluorophenyl)-4-[(2,2-difluoroethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (made by theprocedure described in the synthesis of1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylicacid) (5.0 g, 21.0 mmol) was dissolved in acetonitrile (50 mL). To thiswas added diisopropylethylamine (9.06 mL, 52.6 mmol) followed by2,2-difluoroethylamine (1.93 g, 23.1 mmol) and the resulting mixture wasrefluxed for 2 hours. Then the mixture was cooled to room temperatureand concentrated in vacuo. The resulting residue was dissolved indichloromethane (250 mL) and this was washed with aqueous hydrochloricacid (2×150 mL, 1N). The organics were dried on sodium sulphate,filtered and concentrated in vacuo yielding methyl4-(2,2-difluoroethyl-sulfamoyl)-1-methyl-pyrrole-2-carboxylate (5.4 g)as light brown oil which solidified while standing and was used as such.Methyl 4-(2,2-difluoroethylsulfamoyl)-1-methyl-pyrrole-2-carboxylate(5.4 g, 19.1 mmol) was dissolved in tetrahydrofuran (50 mL). To this wasadded an aqueous solution of lithium hydroxide (0.69 g, 28.7 mmol) indistilled water (7 mL) and a turbid mixture was obtained. Then methanol(3 mL) was added. The resulting mixture was stirred for 24 hours at roomtemperature and at 60° C. for 1 hour. To this was added lithiumhydroxide (0.458 g, 19.1 mmol). The reaction mixture was further heatedat 60° C. for 3 hours. Then it was concentrated to keep ˜5 mL aqueoussolution and extra 15 mL of distilled water was added. Then this wasneutralized using an exact amount of hydrochloric acid (47.8 mL, 47.83mmol/1M/aq/). The resulting mixture was extracted usingmethyltetrahydrofuran (3×20 mL). The combined extracts were dried onsodium sulphate, filtered and concentrated in vacuo yielding of4-(2,2-difluoroethylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (4.88g) as white powder which was used as such. ¹H NMR (400 MHz, DMSO-d₆) δppm 3.15 (tdd, J=15.4, 15.4, 6.4, 4.0 Hz, 2H), 3.88 (s, 3H), 5.99 (tt,J=55.7, 4.2 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H),7.84 (t, J=6.4 Hz, 1H).4-(2,2-difluoroethylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (500mg, 1.77 mmol) and 5-amino-2-fluorobenzonitrile (0.5 g, 3.54 mmol) andHATU (0.81 g, 2.12 mmol) were dissolved in DMF (2.5 mL) containingdiisopropylethylamine (1. 22 mL, 7.08 mmol). The reaction mixture wasstirred at room temperature for 66 hours. The reaction mixture wasdirectly loaded on column and purified using silica gel columnchromatography (ethyl acetate in heptane from 20 to 80%). The desiredfractions were combined and evaporated to keep ˜50 mL of the solvent and20 mL of diethyl ether was added. The formed precipitate was filteredand washed with diethyl ether to afford compound 126 (412 mg) as whitesolid. Method B; Rt: 0.88 min. m/z: 385 (M−H)⁻ Exact mass: 386.07. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.20 (td, J=15.3, 4.0 Hz, 2H), 3.92 (s,3H), 6.02 (tt, J=55.7, 4.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.53 (t,J=9.1 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.93 (br. s, 1H), 8.01 (ddd,J=9.2, 5.0, 2.8 Hz, 1H), 8.21 (dd, J=5.7, 2.6 Hz, 1H), 10.36 (br. s.,1H).

Compound 127:N-(3-Bromo-4-fluorophenyl)-4-[(2,2-difluoroethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 127 (452 mg) as white powder was synthesized similarly asdescribed for compound 126 using 3-bromo-4-fluoroaniline instead of5-amino-2-fluorobenzonitrile in the last step. Method B; Rt: 1.00 min.m/z: 438 (M−H)⁻ Exact mass: 438.98. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20(td, J=15.3, 4.0 Hz, 2H), 3.92 (s, 3H), 6.02 (tt, J=55.5, 4.0 Hz, 1H),7.34-7.39 (m, 2H), 7.63 (d, J=1.5 Hz, 1H), 7.70 (ddd, J=9.0, 4.4, 2.6Hz, 1H), 7.88 (br. s., 1H), 8.14 (dd, J=6.5, 2.5 Hz, 1H), 10.21 (br. s.,1H).

Compound 128:N-(3-Chloro-4-fluorophenyl)-4-[(2,2-difluoroethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 128 (372 mg) as white powder was synthesized similarly asdescribed for compound 126 using 3-chloro-4-fluoroaniline instead of5-amino-2-fluorobenzonitrile in the last step. Method B; Rt: 0.99 min.m/z: 394 (M−H)⁻ Exact mass: 395.03. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20(td, J=15.3, 4.0 Hz, 2H), 3.92 (s, 3H), 6.02 (tt, J=55.7, 4.0 Hz, 1H),7.35 (d, J=1.8 Hz, 1H), 7.40 (t, J=9.1 Hz, 1H), 7.61-7.69 (m, 2H), 7.89(br. s., 1H), 8.02 (dd, J=6.9, 2.5 Hz, 1H), 10.22 (br. s., 1H).

Compound 129:4-[(2,2-Difluoroethyl)sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 129 (371 mg) as white powder was synthesized similarly asdescribed for compound 126 using 3,4-difluoroaniline instead of5-amino-2-fluorobenzonitrile in the last step. Method B; Rt: 0.94 min.m/z: 378 (M−H)⁻ Exact mass: 379.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20(td, J=15.2, 4.1 Hz, 2H), 3.92 (s, 3H), 6.02 (tt, J=55.5, 4.0 Hz, 1H),7.34 (d, J=2.0 Hz, 1H), 7.41 (dt, J=10.3, 9.0 Hz, 1H), 7.46-7.53 (m,1H), 7.64 (d, J=1.8 Hz, 1H), 7.79-7.94 (m, 2H), 10.24 (br. s., 1H).

Compound 130:N-(3-Chloro-4,5-difluorophenyl)-4-[(2,2-difluoroethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 130 was synthesized similarly as described for compound 126. Inthe last step, 3-chloro-4,5-difluoroaniline hydrochloride (synthesisdescribed in synthesis for compound 57) instead of5-amino-2-fluorobenzonitrile was used and the reaction time was 18 hoursinstead of 66 hours. The reaction mixture was purified using silica gelcolumn chromatography (gradient elution: ethyl acetate in heptane from 0to 100% and from 30 to 50%). The purest fractions were combined andstored as such for 66 hours. White precipitates were filtered and washedwith heptane to afford a white solid. The solids were dissolved inmethanol and concentrated to dryness to afford a white powder which waswarm triturated in methanol (3 mL) and cooled to room temperature. Thewhite solids were filtered and washed with methanol to afford compound130 (131 mg) as white powder. Method B; Rt: 0.94 min. m/z: 412 (M−H)⁻Exact mass: 413.02.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20 (td, J=15.3, 4.0 Hz, 2H), 3.91 (s,3H), 6.02 (tt, J=55.7, 4.0 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.49-8.27(m, 4H), 10.31 (br. s., 1H).

Compound 131:N-(3-Chloro-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoroethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (made by theprocedure described in the synthesis of1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylicacid) (5.0 g, 21.0 mmol) was dissolved in acetonitrile (50 mL). To thiswas added DIPEA (9.06 mL, 52.6 mmol) followed by2,2,2-trifluoroethylamine (2.29 g, 23.1 mmol) and the resulting mixturewas refluxed for 2 hours. Then the mixture was cooled to roomtemperature and concentrated in vacuo. The resulting residue wasdissolved in dichloromethane (250 mL) and this was washed with aqueoushydrochloric acid (2×150 mL, 1N). The organics were dried on sodiumsulphate, filtered and concentrated in vacuo yielding methyl1-methyl-4-(2,2,2-trifluoroethyl-sulfamoyl)pyrrole-2-carboxylate (5.3 g)as light brown oil which solidified while standing and was used as such.Methyl 1-methyl-4-(2,2,2-trifluoroethylsulfamoyl)pyrrole-2-carboxylate(5.3 g, 17.65 mmol) was dissolved in tetrahydrofuran (50 mL) and asolution of lithium hydroxide (0.634 g, 26.5 mmol) in distilled water (7mL) was added and a turbid mixture was obtained. Then methanol (3 mL)was added and the mixture became clear. The resulting mixture wasstirred at room temperature for 24 hours and at 60° C. for 1 hour. Tothis was added lithium hydroxide (0.423 g, 17.7 mmol). The reactionmixture was further heated at 60° C. for 3 hours. Then the reactionmixture was concentrated to keep ˜5 mL and distilled water (15 mL) wasadded. The mixture was neutralized using an exact amount of hydrochloricacid (1M/aq/31.6 mL, 31.58 mmol). The resulting mixture was extractedusing methyltetrahydrofuran (3×20 mL). The combined extracts were driedon sodium sulphate, filtered and concentrated in vacuo yielding1-methyl-4-(2,2,2-trifluoroethylsulfamoyl)pyrrole-2-carboxylic acid(4.62 g) as beige powder which was used as such.1-methyl-4-(2,2,2-trifluoroethylsulfamoyl)pyrrole-2-carboxylic acid (500mg, 1.66 mmol) and 3-chloro-4-fluoroaniline (0.48 g, 3.32 mmol) and HATU(0.76 g, 1.99 mmol) were dissolved in DMF (2 mL) containingdiisopropylethylamine (1.14 mL, 6.64 mmol). The reaction mixture wasstirred at room temperature for 66 hours. The reaction mixture wasdirectly loaded on column and purified using silica gel columnchromatography (ethyl acetate in heptane from 20 to 80%). The desiredfractions were combined and evaporated to keep ˜50 mL of the solvent and20 mL of diethyl ether was added. The formed precipitate was filteredand washed with diethyl ether to afford an off white solid which wasrecrystallized from acetonitrile (5 mL) to afford compound 131 (117 mg)as white solid. Method B; Rt: 1.03 min. m/z: 412 (M−H)⁻ 431 (M+18) Exactmass: 413.02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62 (q, J=9.5 Hz, 2H),3.91 (s, 3H), 7.31-7.45 (m, 2H), 7.61-7.70 (m, 2H), 8.02 (dd, J=6.8, 2.6Hz, 1H), 8.27 (br. s., 1H), 10.23 (br. s, 1H).

Compound 132:N-(3,4-Difluorophenyl)-1-methyl-4-[(2,2,2-trifluoroethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 132 was synthesized similarly as described for compound 131using 3,4-difluoroaniline (433 mg, 3.32 mmol) instead of3-chloro-4-fluoroaniline in the last step. The off white solid wasrecrystallized from methanol to afford compound 132 (208 mg) as whitepowder. Method B; Rt: 0.98 min. m/z: 396 (M−H)⁻ Exact mass: 397.05. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.62 (q, J=9.6 Hz, 2H), 3.91 (s, 3H), 7.35(d, J=1.8 Hz, 1H), 7.41 (dt, J=10.5, 9.1 Hz, 1H), 7.45-7.52 (m, 1H),7.65 (d, J=1.8 Hz, 1H), 7.87 (ddd, J=13.4, 7.5, 2.4 Hz, 1H), 8.26 (br.s., 1H), 10.24 (s, 1H).

Compound 133:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-[(2,2,2-trifluoroethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 133 was synthesized similarly as described for compound 131.3-chloro-4,5-difluoroaniline hydrochloride (664 mg, 332 mmol) (synthesisdescribed in synthesis for compound 57) was used instead of3-chloro-4-fluoroaniline in the last step. The reaction mixture wasdirectly loaded on column and purified using silica gel columnchromatography (ethyl acetate in heptane from 0 to 100%) The purestfractions were combined and stored as such for 66 hours. Off whitecrystals were formed and filtered and washed with heptane to afford abeige solid. The solid was triturated in diethyl ether (15 mL) andfiltered and washed with diethyl ether to afford a white powder. Thewhite powder was purified using silica gel column chromatography(methanol in CH₂Cl₂ from 0 to 2%) The purest fractions were combined andconcentrated to dryness to afford compound 133 (41 mg) as white powder.Method B; Rt: 1.09 min. m/z: 430 (M−H)⁻ 863 (2M+H) Exact mass: 431.01.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62 (q, J=9.6 Hz, 2H), 3.91 (s, 3H),7.36 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.77-7.85 (m, 2H), 8.29(br. s., 1H), 10.32 (br. s., 1H).

Compound 134:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoroethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 134 was synthesized similarly as described for compound 131using 5-amino-2-fluorobenzonitrile (466 mg, 3.32 mmol) instead of3-chloro-4-fluoroaniline in the last step. The reaction mixture wasdirectly loaded on column and purified using silica gel columnchromatography (ethyl acetate in heptane from 20 to 80%). The desiredfractions were combined and evaporated to keep ˜50 mL of the solvent and20 mL of diethyl ether was added. The formed precipitate was filteredand washed with diethyl ether to afford an off white solid which waspurified using Prep. LCMS. (Hypersyl C18 BDS-3 μm, 100×4.6 mm) Mobilephase (NH₄HCO₃ 0.2% in water, acetonitrile) the desired fractions werecombined and evaporated to dryness, dissolved in methanol again andevaporated to dryness and dried in vacuum oven overnight to affordcompound 134 (147 mg) as white powder. Method B; Rt: 0.93 min. m/z: 403(M−H)⁻ Exact mass: 404.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.61 (q,J=9.5 Hz, 2H), 3.92 (s, 3H), 7.37 (d, J=2.0 Hz, 1H), 7.53 (t, J=9.1 Hz,1H), 7.66 (d, J=1.5 Hz, 1H), 8.00 (ddd, J=9.2, 4.9, 2.9 Hz, 1H), 8.33(br. s, 1H), 8.22 (dd, J=5.9, 2.6 Hz, 1H), 10.38 (br. s., 1H).

Compound 135:N-(3-Bromo-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoroethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 135 was synthesized similarly as described for compound 134using 3-bromo-4-fluoroaniline (631 mg, 3.32 mmol) instead of5-amino-2-fluorobenzonitrile in the last step. Method B; Rt: 1.04 min.m/z: 456 (M−H)⁻ Exact mass: 456.97. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62(q, J=9.5 Hz, 2H), 3.91 (s, 3H), 7.34-7.40 (m, 2H), 7.65 (d, J=1.8 Hz,1H), 7.70 (ddd, J=9.1, 4.3, 2.4 Hz, 1H), 8.14 (dd, J=6.4, 2.6 Hz, 1H),8.26 (br. s., 1H), 10.21 (br. s, 1H).

Compound 136:N-(3-Chloro-4,5-difluorophenyl)-1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Crude ethyl1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate(described in synthesis of compound 89)(1800 mg, 5.689 mmol) wasdissolved in methanol (8 mL), lithium hydroxide (720 mg, 30.1 mmol) inwater (2 mL) was added and the reaction mixture was heated at 50° C. for2 hours. The reaction mixture was evaporated to dryness and coevaporated with toluene (2×50 mL) to afford a beige powder. Half of theabove obtained powder was dissolved in water (5 mL), and HCl (1M inwater, 15.02 mL) was added. The water layer was extracted with Me-THF(3×20 mL). The combined organic layers were washed with Brine, dried(Na₂SO₄) and concentrated to dryness to afford1,5-dimethyl-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-pyrrole-2-carboxylicacid (600 mg).1,5-dimethyl-4-(N-(3-methyloxetan-3-yl)-sulfamoyl)-1H-pyrrole-2-carboxylicacid (600 mg, 2.08 mmol) was dissolved in DMF (3 mL).diisopropylethylamine (1.08 mL, 6.24 mmol), HATU (950 mg, 2.50 mmol),and 3-chloro-4,5-difluoroaniline hydrochloride (described in thesynthesis of compound 57) were added and the reaction mixture wasstirred at room temperature for 68 hours and at 60° C. for 2 hours. Thereaction mixture was directly loaded on column. The reaction mixture waspurified using silica gel column chromatography (ethyl acetate inheptane from 20 to 80%). The desired fraction were combined andconcentrated to keep ˜100 mL of solvent. The white precipitate wasfiltered and washed with petroleum ether and dried in vacuum ovenovernight to afford compound 136 (604 mg) as white powder. Method B; Rt:1.03 min. m/z: 432 (M−H)⁻ Exact mass: 433.07. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.49 (s, 3H), 2.44 (s, 3H), 3.83 (s, 3H), 4.11 (d, J=6.4 Hz, 2H),4.59 (d, J=5.9 Hz, 2H), 7.35 (s, 1H), 7.77-7.86 (m, 2H), 7.97 (s, 1H),10.20 (s, 1H).

Compound 137:N-(3-Chloro-4,5-difluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

In a pressure tube, crude ethyl4-chlorosulfonyl-1,5-dimethyl-pyrrole-2-carboxylate (3.03 g, 11.4 mmol)(synthesis described in synthesis for compound 89) was dissolved inacetonitrile (30 mL). To this was added diisopropylethylamine (4.91 mL,28.5 mmol) followed by (R)-1,1,1-trifluoro-2-propylamine (3.22 g, 28.5mmol) and the tube was closed and resulting mixture was heated at 80° C.for 2 hours. The reaction mixture was concentrated and the resultingorange sticky oil was dissolved in dichloromethane (50 mL) and this waswashed with aqueous hydrochloric acid (1N, 2×20 mL). The organics weredried on sodium sulphate, filtered and concentrated in vacuo yieldingorange oil (3.41 g) which was purified using silica gel columnchromatography (ethyl acetate in heptane from 0 to 80%). The desiredfractions were combined and evaporated to dryness to afford (R)-ethyl1,5-dimethyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxylate(2.3 g) as white powder which was used as such. (R)-ethyl1,5-dimethyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxylate(2.3 g, 6.72 mmol) was dissolved in ethanol (30 mL) and sodium hydroxidein water (13.4 mL, 13.4 mmol, 1 M) was added and the reaction mixturewas stirred at 40° C. for 2 hours and at room temperature for 66 hours.The reaction mixture was heated at 70° C. for 2 hours. Sodium hydroxidein water (6.72 mL, 6.72-mmol, 1 M) was added to the reaction mixturewhich was heated at 70° C. for 2 hours more. The reaction mixture wasallowed to reach room temperature and was concentrated to keep ˜20 mL.HCl (20.15 mL, 20.15 mmol, 1M) was added. The water layer was extractedwith Me-THF (3×20 mL). The combined organic layers were washed withBrine, dried (Na₂SO₄) and concentrated to dryness to afford(R)-1,5-dimethyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxylicacid (2.05 g).(R)-1,5-dimethyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxylicacid (450 mg, 1.43 mmol) and 3-chloro-4,5-difluoroaniline hydrochloride(0.57 g, 2.86 mmol) (synthesis described in synthesis for compound 57)and HATU (0.73 g, 1.91 mmol) were dissolved in DMF (2 mL) containingdiisopropylethylamine (0.82 mL, 4.77 mmol). The reaction mixture wasstirred at 40° C. for 66 hours. The reaction mixture was directly loadedon column. The reaction mixture was purified using silica gel columnchromatography (ethyl acetate in heptane from 20 to 80%). The desiredfractions were combined and evaporated to keep ˜50 mL of solvent. Theprecipitates were filtered and washed with petroleum ether and dried invacuum oven at 50° C. overnight to afford compound 137 (490 mg) as whitepowder. Method B; Rt: 1.16 min. m/z: 458 (M−H)⁻ 460 (M+H)⁺ Exact mass:459.04. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.8 Hz, 3H), 2.44 (s,3H), 3.69-3.95 (m, 4H), 7.37 (s, 1H), 7.76-7.86 (m, 2H), 8.21 (br. s.,1H), 10.24 (br. s., 1H).

Compound 138:N-(3-Chloro-4-fluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 138 (510 mg) as white powder was synthesized similarly asdescribed for compound 137 using 3-chloro-4-fluoroaniline instead of3-chloro-4,5-difluoroaniline hydrochloride in the last step. Method B;Rt: 1.10 min. m/z: 440 (M−H)⁻ Exact mass: 441.05. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.07 (d, J=7.0 Hz, 3H), 2.44 (s, 3H), 3.75-3.87 (m, 4H),7.36 (s, 1H), 7.39 (t, J=9.1 Hz, 1H), 7.66 (ddd, J=9.1, 4.3, 2.6 Hz,1H), 8.02 (dd, J=6.9, 2.5 Hz, 1H), 8.19 (br. s, 1H), 10.15 (s, 1H).

Compound 139:N-(3,4-Difluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 139 (462 mg) as white powder was synthesized similarly asdescribed for compound 137 using 3,4-difluoroaniline instead of3-chloro-4,5-difluoroaniline hydrochloride in the last step. Method B;Rt: 1.06 min. m/z: 424 (M−H)⁻ 426 (M+H)⁺ Exact mass: 425.08. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.8 Hz, 3H), 2.44 (s, 3H), 3.75-3.88 (m,4H), 7.35 (s, 1H), 7.40 (dt, J=10.5, 9.2 Hz, 1H), 7.45-7.54 (m, 1H),7.87 (ddd, J=13.4, 7.6, 2.5 Hz, 1H), 8.19 (br. s., 1H), 10.17 (s, 1H).

Compound 140:N-(3-Cyano-4-fluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

(R)-1,5-dimethyl-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)-1H-pyrrole-2-carboxylicacid (168 mg, 0.53 mmol) (synthesis described in synthesis for compound137) 5-amino-2-fluorobenzonitrile (0.15 g, 1.07 mmol) and HATU (0.24 g,0.64 mmol) were dissolved in DMF (1 mL) containing diisopropylethylamine(0.23 mL, 1.34 mmol). The reaction mixture was stirred at 50° C. for 1hour. The reaction mixture was purified using silica gel columnchromatography (ethyl acetate in heptane from 20 to 80%). The desiredfractions were combined and evaporated to keep ˜50 mL of the solvent.The white solids were filtered and dried in vacuum oven to affordcompound 140 (180 mg) as white powder. Method B; Rt: 1.00 min. m/z: 431(M−H)⁻ Exact mass: 432.09. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d,J=6.8 Hz, 3H), 2.44 (s, 3H), 3.76-3.87 (m, 1H), 3.84 (s, 3H), 7.38 (s,1H), 7.52 (t, J=9.1 Hz, 1H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1H),8.10-8.35 (m, 1H), 8.22 (dd, J=5.9, 2.6 Hz, 1H), 10.30 (br. s, 1H).

Compound 141:N-(3-Bromo-4-fluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 141 (210 mg) as white powder was synthesized similarly asdescribed for compound 140 using 3-bromo-4-fluoroaniline (0.20 g, 1.07mmol) instead of 5-amino-2-fluorobenzonitrile. Method B; Rt: 1.11 min.m/z: 484 (M−H)⁻ Exact mass: 485.00. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07(d, J=7.0 Hz, 3H), 2.43 (s, 3H), 3.74-3.89 (m, 1H), 3.83 (s, 3H),7.29-7.40 (m, 2H), 7.70 (ddd, J=9.0, 4.4, 2.6 Hz, 1H), 8.13 (dd, J=6.4,2.6 Hz, 1H), 8.18 (br. s., 1H), 10.13 (s, 1H).

Compound 142:N-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 142 (187 mg) as white powder was synthesized similarly asdescribed for compound 140 using 4-fluoro-3-(trifluoromethyl)aniline(0.19 g, 1.07 mmol) instead of 5-amino-2-fluorobenzonitrile. Method B;Rt: 1.14 min. m/z: 474 (M−H)⁻ Exact mass: 475.08. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.07 (d, J=7.0 Hz, 3H), 2.44 (s, 3H), 3.76-3.85 (m, 1H),3.84 (s, 3H), 7.39 (s, 1H), 7.49 (br. t, J=9.8, 9.8 Hz, 1H), 8.00-8.08(m, 1H), 8.10-8.30 (m, 1H), 8.19 (dd, J=6.6, 2.6 Hz, 1H), 10.28 (s, 1H).

Compound 143:N-(3-Chloro-2,4-difluorophenyl)-1,5-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 143 (147 mg) as white powder was synthesized similarly asdescribed for compound 140 using 3-chloro-2,4-difluoroaniline (0.17 g,1.07 mmol) instead of 5-amino-2-fluorobenzonitrile. The reaction mixturewas stirred at 60° C. for 2 hours more. Method B; Rt: 1.07 min. m/z: 458(M−H)⁻ Exact mass: 459.04. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d,J=7.0 Hz, 3H), 2.44 (s, 3H), 3.82 (s, 3H), 3.76-3.91 (m, 1H), 7.34 (td,J=9.0, 2.0 Hz, 1H), 7.35 (s, 1H), 7.52 (td, J=8.7, 5.8 Hz, 1H), 8.20(br. s., 1H), 10.05 (s, 1H).

Synthesis of ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate(step 1)

Ethyl 1, 3-dimethylpyrrole-2-carboxylate (10.7 g, 61.0 mmol) was addeddrop wise to chlorosulfonic acid (33.3 mL, 500 mmol) at 0° C. undernitrogen atmosphere. The reaction mixture was warmed to room temperatureand allowed to stir 2 hours. The resulting mixture was added drop wiseto a stirred, temperature controlled ice-water mixture (200 mL) keepingthe temperature under 5° C. A white precipitation was formed. Theobtained aqueous suspension was extracted using dichloromethane (3×100mL). The combined extracts were washed with Brine and dried on sodiumsulphate, filtered and concentrated in vacuo yielding ethyl4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate (13.96 g) as a brownpowder which was used as such. Method B; Rt: 1.11 min. m/z: 264 (M−H)⁻Exact mass: 265.02.

Synthesis of Ethyl1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(step 2)

In a pressure tube, ethyl4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate (4.65 g, 17.5 mmol)was dissolved in acetonitrile (30 mL). To this was addeddiisopropylethylamine (7.54 mL, 43.8 mmol) followed by(R)-1,1,1-trifluoro-2-propylamine (2.97 g, 26.3 mmol) and the tube wasclosed and resulting mixture was heated at 80° C. overnight. Then themixture was cooled to room temperature and concentrated. The resultingbrown sticky oil was dissolved in dichloromethane (100 mL) and this waswashed with hydrochloric acid (1N, 2×30 mL). The organics were dried onsodium sulphate, filtered and concentrated in vacuo yielding brown oil(5.12 g). The brown oil was purified using silica gel columnchromatography (gradient elution: ethyl acetate:heptane from 0 to 80%).The desired fractions were combined and evaporated to dryness to affordethyl1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(3.05 g) as light yellow powder. Method B; Rt: 0.96 min. m/z: 341 (M−H)⁻Exact mass: 342.09.

Synthesis of1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (Step 3)

Ethyl1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(3.05 g, 8.46 mmol) was dissolved in ethanol (50 mL) and sodiumhydroxide in water (1 M, 42.3 mL, 42.3 mmol) was added. The reactionmixture was stirred at 80° C. for 18 hours. The reaction mixture wasallowed to reach room temperature and was concentrated to keep ˜20 mLsolvent. The solution was diluted with aqueous hydrochloride (1 M, 42.3mL, 42.3 mmol) and extracted with Me-THF (3×30 mL). The combined organiclayers were washed with Brine, dried (Na₂SO₄) and concentrated todryness to afford1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (2.71 g). Method B; Rt: 0.45 min. m/z: 313 (M−H)⁻ Exact mass:314.05.

Compound 144:N-(3,4-Difluorophenyl)-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide(step 4)

1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (450 mg, 1.43 mmol) and 3,4-difluoroaniline (0.37 g, 2.86 mmol) andHATU (0.73 g, 1.91 mmol) were dissolved in DMF (1.92 mL, 24.7 mmol)containing diisopropylethylamine (0.82 mL, 4.77 mmol). The reactionmixture was stirred at 40° C. for 42 hours and allowed to reach roomtemperature. The reaction mixtures were purified using silica gel columnchromatography (gradient elution: ethyl acetate in heptane from 10 to70%). The desired fractions were combined and evaporated to keep ˜50 mLof the solvent. The white solids were filtered and dried overnight invacuum oven at 50° C. to afford compound 144 (470 mg) as white powder.Method B; Rt: 1.01 min. m/z: 424 (M−H)⁻ Exact mass: 425.08. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz, 3H), 2.29 (s, 3H), 3.72 (s, 3H),3.82 (quin, J=7.5 Hz, 1H), 7.37-7.46 (m, 2H), 7.50 (s, 1H), 7.73-7.92(m, 1H), 8.16 (br. s., 1H), 10.31 (s, 1H).

Compound 145:N-(3-Chloro-4-fluorophenyl)-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 145 (452 mg) as white powder was synthesized similarly asdescribed for compound 144 using 3-chloro-4-fluoroaniline instead of3,4-difluoroaniline. Method B; Rt: 1.06 min. m/z: 440 (M−H)⁻ Exact mass:441.05. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz, 3H), 2.30 (s,3H), 3.72 (s, 3H), 3.83 (quin, J=6.6 Hz, 1H), 7.41 (t, J=9.1 Hz, 1H),7.50 (s, 1H), 7.55-7.71 (m, 1H), 7.98 (dd, J=6.7, 2.1 Hz, 1H), 8.16 (br.s., 1H), 10.29 (s, 1H).

Compound 146:N-(3,4-Difluorophenyl)-1,3-dimethyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 146 (353 mg) as white powder was synthesized similarly asdescribed for compound 144 using (S)-1,1,1-trifluoro-2-propylamine (1.50g, 13.3 mmol) instead of (R)-1,1,1-trifluoro-2-propylamine in Step 2(resulting in1,3-dimethyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid as intermediate). Method B; Rt: 1.01 min. m/z: 424 (M−H)⁻ Exactmass: 425.08. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz, 3H),2.29 (s, 3H), 3.72 (s, 3H), 3.76-3.87 (m, 1H), 7.34-7.46 (m, 2H), 7.49(s, 1H), 7.74-7.91 (m, 1H), 8.16 (br. s., 1H), 10.31 (s, 1H).

Compound 147:N-(3-Chloro-4-fluorophenyl)-1,3-dimethyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 147 (443 mg) as white powder was synthesized similarly asdescribed for compound 144 using (S)-1,1,1-trifluoro-2-propylamine (1.50g, 13.3 mmol) instead of (R)-1,1,1-trifluoro-2-propylamine in Step 2(resulting in1,3-dimethyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid as intermediate) and 3-chloro-4-fluoroaniline instead of3,4-difluoroaniline in Step 4. Method B; Rt: 1.06 min. m/z: 440 (M−H)⁻Exact mass: 441.05. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=7.0 Hz,3H), 2.30 (s, 3H), 3.72 (s, 3H), 3.83 (quin, J=7.2 Hz, 1H), 7.41 (t,J=9.1 Hz, 1H), 7.50 (s, 1H), 7.62 (ddd, J=9.0, 4.2, 2.6 Hz, 1H), 7.98(dd, J=6.8, 2.4 Hz, 1H), 8.17 (br. s., 1H), 10.29 (s, 1H).

Compound 148:N-(3,4-Difluorophenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 148 was synthesized similarly as described for compound 144using 3-methyl-3-oxetanamine instead of(R)-1,1,1-trifluoro-2-propylamine in Step 2. In Step 4, the desiredfractions were evaporated to afford oil which was purified again usingsilica gel column chromatography (gradient elution: ethyl acetate inheptane from 40 to 70%). The desired fractions were combined andevaporated to afford compound 148 (475 mg) as white powder. Method B;Rt: 0.86 min. m/z: 398 (M−H)⁻ Exact mass: 399.11. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.53 (s, 3H), 2.32 (s, 3H), 3.72 (s, 3H), 4.13 (d, J=6.4Hz, 2H), 4.62 (d, J=5.9 Hz, 2H), 7.36-7.51 (m, 3H), 7.62-8.16 (m, 2H),10.32 (br. s., 1H).

Compound 149:N-(3-Chloro-4-fluorophenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 149 was synthesized as compound 144 using3-methyl-3-oxetanamine instead of (R)-1,1,1-trifluoro-2-propylamine inStep 2 and 3-chloro-4-fluoroaniline instead of 3,4-difluoroaniline inStep 4. In Step 4, the desired fractions were evaporated to afford oilwhich solidified while standing. The powder was triturated in warmCH₂Cl₂ (10 mL) and allowed to reach room temperature. The white solidswere filtered and washed with CH₂Cl₂ (5 mL) and petroleum ether (5 mL)and dried in vacuum oven at 50° C. to afford compound 149 (435 mg) aswhite powder. Method B; Rt: 0.92 min. m/z: 414 (M−H)⁻ Exact mass:415.08. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s, 3H), 2.32 (s, 3H), 3.72(s, 3H), 4.12 (d, J=6.4 Hz, 2H), 4.62 (d, J=5.9 Hz, 2H), 7.41 (t, J=9.1Hz, 1H), 7.47 (s, 1H), 7.62 (ddd, J=9.0, 4.4, 2.6 Hz, 1H), 7.91 (br. s.,1H), 7.99 (dd, J=6.8, 2.6 Hz, 1H), 10.29 (br. s., 1H).

Compound 150:N-(3-Cyano-4-fluorophenyl)-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 150 (416 mg) as white powder was synthesized as compound 144using 5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline andthe reaction time was 20 hours instead of 42 hours in Step 4. Method C;Rt: 1.68 min. m/z: 431 (M−H)⁻ Exact mass: 432.09. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.11 (d, J=7.0 Hz, 3H), 2.31 (s, 3H), 3.73 (s, 3H), 3.83(quin, J=7.2 Hz, 1H), 7.52 (br. s, 1H), 7.54 (t, J=9.1 Hz, 1H), 7.97(ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.09-8.27 (m, 1H), 8.18 (dd, J=5.7, 2.6Hz, 1H), 10.42 (br. s., 1H).

Compound 151:N-(3-Cyano-4-fluorophenyl)-1,3-dimethyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 151 (420 mg) as white powder was synthesized similarly asdescribed for compound 144 using (S)-1,1,1-trifluoro-2-propylamine (1.50g, 13.3 mmol) instead of (R)-1,1,1-trifluoro-2-propylamine in Step 2 and5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline and thereaction time was 20 hours instead of 42 hours in Step 4. Method B; Rt:0.96 min. m/z: 431 (M−H)⁻ Exact mass: 432.09. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.11 (d, J=6.8 Hz, 3H), 2.31 (s, 3H), 3.73 (s, 3H), 3.83 (quin,J=7.2 Hz, 1H), 7.51 (s, 1H), 7.54 (t, J=9.2 Hz, 1H), 7.97 (ddd, J=9.2,4.9, 2.9 Hz, 1H), 8.09-8.27 (m, 1H), 8.18 (dd, J=5.9, 2.6 Hz, 1H), 10.42(br. s., 1H).

Compound 152:N-(3-Cyano-4-fluorophenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 152 was synthesized similarly as described for compound 144using 3-methyl-3-oxetanamine instead of(R)-1,1,1-trifluoro-2-propylamine in Step 2 and5-amino-2-fluorobenzonitrile instead of 3,4-difluoroaniline in Step 4.In Step 4, the desired fractions were evaporated to afford light yellowoil which was purified again using silica gel column chromatography(gradient elution: ethyl acetate in heptane from 40 to 70%). The desiredfractions were combined and evaporated to afford compound 152 (332 mg)as white powder. Method B; Rt: 0.80 min. m/z: 405 (M−H)⁻ Exact mass:406.11. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s, 3H), 2.34 (s, 3H), 3.73(s, 3H), 4.13 (d, J=6.4 Hz, 2H), 4.62 (d, J=5.9 Hz, 2H), 7.48 (s, 1H),7.54 (t, J=9.1 Hz, 1H), 7.92 (br. s., 1H), 7.98 (ddd, J=9.2, 4.9, 2.9Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 10.43 (br. s., 1H).

Compound 153:N-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 153 (270 mg) as beige solid was synthesized similarly asdescribed for compound 144 using1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (260 mg, 0.83 mmol) and 4-fluoro-3-(trifluoromethyl)aniline (0.31g, 1.65 mmol) instead of 3,4-difluoroaniline in Step 4. Method B; Rt:1.10 min. m/z: 474 (M−H)⁻ Exact mass: 475.08. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.12 (d, J=6.8 Hz, 3H), 2.32 (s, 3H), 3.73 (s, 3H), 3.84 (quin,J=7.3 Hz, 1H), 7.48-7.56 (m, 2H), 7.91-8.00 (m, 1H), 8.12-8.24 (m, 2H),10.41 (s, 1H).

Synthesis of methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

In a pressure tube methyl4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (15 g, 63.11 mmol) wasdissolved in 100 mL of dry acetonitrile. To this was added(S)-1,1,1-trifluoro-2-propylamine (8.56 g, 75.74 mmol) followed bydiisopropylethylamine (27.19 mL, 157.79 mmol). The pressure tube wasflushed with nitrogen and closed. The mixture was stirred in apre-heated oil bath at 80° C. for 15 hours. Then it was cooled to roomtemperature and concentrated in vacuo. The obtained residue wasdissolved in dichloromethane (400 mL) and this was washed with HCl(1M/aq/2×100 mL). The obtained organics were dried on Na₂SO₄, filteredand concentrated in vacuo resulting in Methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylateas a beige powder (17.5 g) which was used as such. Method B; Rt: 0.83min. m/z: 313.1 (M−H)⁻ Exact mass: 314.05.

Synthesis of1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicAcid

Methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(6.6 g, 19.7 mmol) was dissolved in tetrahydrofuran (56 mL). To this wasadded lithium hydroxide (1.655 g, 69.1 mmol) in distilled water (7.5 mL)followed by methanol (3 mL). The resulting mixture was stirredovernight. The mixture was concentrated until only water remained andextra distilled water (15 mL) was added. The mixture was neutralisedwith hydrochloric acid (1M, aq). The resulting mixture was extractedusing 2-methyltetrahydrofuran (3×20 mL). The combined extracts weredried on sodium sulphate, filtered and concentrated in vacuo yielding1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (5.34 g). Method B; Rt: 0.45 min. m/z: 299.0 (M−H)⁻ Exact mass:300.04.

Compound 154:1-Methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-N-(2,3,4-trifluorophenyl)-1H-pyrrole-2-carboxamide

1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (500 mg, 1.67 mmol) was dissolved in of N,N-dimethylformamide (1mL). Then HATU (0.76 g, 2 mmol) was added and this mixture was stirredfor 20 minutes. Then diisopropylethylamine (0.86 mL, 5 mmol) was addedfollowed by 2,3,4-trifluoroaniline (0.49 g, 3.33 mmol). The reactionmixture was stirred at 50° C. for 5 hours. Then this mixture was cooledto room temperature and injected directly onto a silica plug. Themixture was purified by silica gel column chromatography using gradientelution from heptane to EtOAc. (100:0 to 0:100) yielding compound 154 asa white powder (253 mg) Method B; Rt: 0.99 min. m/z: 428.1 (M−H)⁻ Exactmass: 429.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm, 1.09 (d, J=7.0 Hz, 3H),3.90 (s, 3H), 3.91-4.02 (m, 1H), 7.24-7.48 (m, 3H), 7.65 (d, J=1.8 Hz,1H), 7.76-8.97 6 (br.s, 1H), 9.58-11.00 (br.s, 1H).

Compound 155:N-(3-Bromo-2,4-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 155 (314 mg) was prepared similarly as described for compound154 using 3-bromo-2,4-difluoro-aniline (0.69 g, 3.33 mmol) instead of2,3,4-trifluoroaniline resulting in white powder. Method B; Rt: 1.04min. m/z: 490.03 (M−H)⁻ Exact mass: 491.0. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.09 (d, J=7.0 Hz, 3H), 3.90 (s, 3H), 3.91-4.02 (m, 1H), 7.23-7.39(m, 2H), 7.57 (td, J=8.7, 5.9 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 8.18 (br.s., 1H), 10.12 (br. s., 1H).

Compound 156:N-(3-Chloro-2,4-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 156 (289 mg) was prepared similarly as compound 154 using3-chloro-2,4-difluoro-aniline (0.54 g, 3.33 mmol) instead of2,3,4-trifluoroaniline resulting in white powder. Method B; Rt: 1.03min. m/z: 444.11 (M−H)⁻ Exact mass: 445.03. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.09 (d, J=6.8 Hz, 3H), 3.90 (s, 3H), 3.91-4.00 (m, 1H), 7.29-7.43(m, 2H), 7.53 (td, J=8.7, 5.9 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 8.17 (br.s., 1H), 10.14 (br. s., 1H).

Compound 157:N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl]pyrrole-2-carboxamide

Prepared similarly as described for compound 123 using5-amino-2-fluoro-benzonitrile (580.5 mg, 4.14 mmol) instead of3-chloro-4-fluoro-aniline, resulting in compound 157 as a white powder(136 mg). Method B; Rt: 0.96 min. m/z: 417.13 (M−H)⁻ Exact mass: 418.07.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.8 Hz, 3H), 3.82-4.00 (m,4H), 7.36 (d, J=2.0 Hz, 1H), 7.43-7.59 (m, 1H), 7.65 (d, J=1.5 Hz, 1H),7.96-8.04 (m, 1H), 8.05-8.33 (m, 2H), 10.38 (br. s., 1H).

Compound 158:N-(3-Cyanophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]-sulfamoyl}-1H-pyrrole-2-carboxamide

To methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(5.0 g, 15.91 mmol, prepared as in the synthesis for compound 122)dissolved in dioxane (59 mL) and water (10 mL) was added LiOH (2.34 g,55.68 mmol) and the reaction mixture stirred 16 h. The mixture wasconcentrated in vacuo. The residue was dissolved in water and acidifiedwith 1N HCl solution till pH-3. The mixture was stirred at roomtemperature for 30′. The product was filtered off and dried in vacuo tobecome a pale yellow solid of1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (3.95 g). This acid (700 mg, 2.33 mmol), 3-aminobenzonitrile (347.8mg, 2.91 mmol), HATU (1108 mg, 2.914 mmol) and DIPEA (1.2 mL, 6.99 mmol)was dissolved in DMF (7 mL) and the mixture was stirred at roomtemperature for 16 h. The mixture was poured in 100 mL ice water and wasextracted with EtOAc. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified on a silica using a gradient eluent Heptane-EtOAc100-0->50-50. The product fractions were collected and concentrated invacuo. The product was crystallized from 2-propanol, filtered off anddried in vacuo, yielding compound 158 (518 mg) as a white solid. MethodB; Rt: 0.93 min. m/z: 399.1 (M−H)⁻ Exact mass: 400.08 ¹H NMR (600 MHz,DMSO-d₆) δ ppm 1.08 (d, J=7.04 Hz, 3H) 3.86-4.00 (m, 4H) 7.39 (d, J=1.91Hz, 1H) 7.50-7.61 (m, 2H) 7.66 (d, J=1.61 Hz, 1H) 7.99 (dt, J=7.56, 2.02Hz, 1H) 8.12-8.21 (m, 2H) 10.35 (s, 1H).

Compound 159:N-[2-Fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 159 (582 mg) was prepared similarly as described for compound158 using 3-amino-2-fluorobenzotrifluoride (0.387 mL, 2.91 mmol) insteadof 3-aminobenzonitrile resulting in a white solid. Method B; Rt: 1.06min. m/z: 460.1 (M−H)⁻ Exact mass: 461.06. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.10 (d, J=6.8 Hz, 3H), 3.87-3.98 (m, 4H), 7.37-7.47 (m, 2H),7.61-7.67 (m, 2H), 7.88 (t, J=7.2 Hz, 1H), 8.19 6 (d, J=8.4 Hz, 1H),10.21 (s, 1H).

Compound 160:N-(3-Cyano-2-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 160 (202 mg) was was prepared similarly as described forcompound 158 using 3-amino-2-fluorobenzonitrile (396.7 mg, 2.91 mmol)instead of 3-aminobenzonitrile resulting in a white solid. Method B; Rt:0.92 min. m/z: 417.1 (M−H)⁻ Exact mass: 418.07. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10 (d, J=7.0 Hz, 3H), 3.89-3.99 (m, 4H), 7.38 (d, J=2.0Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 6 7.78 (ddd,J=7.8, 5.9, 1.5 Hz, 1H), 7.88-7.93 (m, 1H), 8.19 (d, J=8.6 Hz, 1H),10.26 (s, 1H).

Compound 161:N-[3-(1,1-Difluoroethyl)-4-fluorophenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Synthesis of 2-(1,1-difluoroethyl)-1-fluoro-4-nitro-benzene:1-(2-fluoro-5-nitrophenyl)ethanone (19 g, 103.7 mmol) was dissolved indichloromethane (300 mL) The mixture was stirred at −78° C. underN₂-atmosphere. Diethylamino)sulfur trifluoride (33.4 g, 207 mmol) wasadded to the mixture via cannula over a period of 30 min. The reactionmixture was stirred at 35° C. for 16 h. The cold reaction mixture waspoured into ice water (200 mL). The aqueous layer was extracted withdichloromethane (80 mL) twice. The combined organic layers were washedwith water, dried over sodium sulfate and evaporated to dryness toprovide a yellow oil. The crude product was purified by columnchromatography to provide a yellow oil (13 g).

Synthesis of 3-(1,1-difluoroethyl)-4-fluoro-aniline

2-(1,1-difluoroethyl)-1-fluoro-4-nitrobenzene: (13 g, 63.37 mmol) wasdissolved in methanol (65 mL) and water (65 mL). Iron powder (10.6 g)and HCl (25 mL) were added. The mixture was stirred at room temperaturefor 45 min. The reaction mixture was then filtered through celite, thefiltrate was washed with saturated solution of sodium carbonate anddried over sodium sulfate and evaporated to dryness to provide a yellowoil. The crude product was purified by column chromatography to providea yellow oil (5845 mg).

Synthesis of5-[[3-(1,1-difluoroethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride

3-(1,1-difluoroethyl)-4-fluoro-aniline (1099.8 mg, 6.28 mmol) dissolvedin toluene (10 mL) was added dropwise during 5′ to a solution of4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride (1520 mg, 6.28mmol) in toluene (100 mL) at reflux. The reaction mixture was refluxed90 minutes and then concentrated in vacuo, yielding a brown powder whichwas used as such. (2566 mg) Method A; Rt: 2.01 min. m/z: 378.9 (M−H)⁻Exact mass: 380.02.

3-methyloxetan-3-amine (390 mg, 4.47 mmol) was added to a solution of5-[[3-(1,1-difluoroethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (605 mg, 1.49 mmol) in CH₃CN (50 mL) and stirred 17 hr. Waterwas added until crystallisation began. The white powder was filtered offand dried overnight in vacuo at 50° C., resulting in compound 161 (514mg); Method A; Rt: 1.70 min. m/z: 430.1 (M−H)⁻ Exact mass: 431.11. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.55 (s, 3H), 1.95-2.06 (m, 3H), 3.92 (s,3H), 4.14 (d, J=6.4 Hz, 2H), 4.60 (d, J=5.9 Hz, 2H), 7.35 (d, J=2.0 Hz,2H), 7.59 (d, J=1.8 Hz, 1H), 7.85-7.92 (m, 1H), 7.93-8.02 (m, 2H), 10.23(s, 1H).

Compound 162:4-(tert-Butylsulfamoyl)-N-[3-(1,1-difluoroethyl)-4-fluorophenyl]-1-methyl-1H-pyrrole-2-carboxamide

tert-butylamine (400.6 mg, 5.48 mmol) was added to a solution of5-[[3-(1,1-difluoroethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (622 mg, 1.53 mmol) in CH₃CN (50 mL) and stirred 17 hr. Waterwas added until crystallisation began. The white powder was filtered offand dried overnight in vacuo at 50° C., resulting in compound 162 (355mg). Method A; Rt: 1.91 min. m/z: 416.1 (M−H)⁻ Exact mass: 417.13. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 1.93-2.08 (m, 3H), 3.91 (s,3H), 7.11 (s, 1H), 7.27-7.37 (m, 2H), 7.52 (d, J=1.5 Hz, 1H), 7.85-7.936 (m, 1H), 7.96-8.02 (m, 1H), 10.21 (s, 1H).

Compound 163:N-(3,5-Dichloro-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

3,5-dichloro-4-fluoroaniline (1534 mg, 18.52 mmol) dissolved in toluene(10 mL) was added to 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonylchloride (2063 mg, 8.52 mmol) in toluene (125 mL) at reflux and refluxed2 hours. The reaction mixture was filtered while still hot andconcentrated yielding a crude beige powder (2833 mg,5-[(3,5-dichloro-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride) which was used as such. ¹H NMR (400 MHz, ACETONITRILE-d₃) δppm 3.96 (s, 3H), 7.39 (d, J=2.0 Hz, 1H), 7.71-7.77 (m, 3H), 8.78 (br.s., 1H)

2,2,2-trifluoro-1,1-dimethyl-ethylamine (692 mg, 5.45 mmol) was added to5-[(3,5-dichloro-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (700.2 mg, 1.82 mmol) and DIPEA (0.47 mL, 2.72 mmol) dissolvedin CH₃CN (66 mL) and refluxed overnight. The reaction mixture wasconcentrated. The residue was dissolved in EtOAc, washed with 1M HCl,dried over sodium sulphate, filtered and concentrated. The residue waspurified by column chromatography on silica using a gradient from 10till 100% EtOAc in heptane. The obtained powder was recrystallized frommethanol (25 mL), upon addition of water and further purified by by PrepHPLC (Stationary phase: RP XBridge Prep C18 OBD-10 m, 30×150 mm), Mobilephase: 0.25% NH₄HCO₃ solution in water, MeOH), yielding a white powderwhich was dried in vacuo at 50° C. during 6 hours. Method A; Rt: 2.13min. m/z: 473.9 (M−H)⁻ Exact mass: 475.01. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.36 (s, 6H), 3.92 (s, 3H), 7.34 (d, J=2.0 Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.95 (d, J=6.2 Hz, 2H), 8.07 (s, 1H), 6 10.30 (s, 1H).

Compound 164:N-(3-Chloro-4,5-difluorophenyl)-4-[(3,3-difluorocyclobutyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (561.7 mg, 1.15 mmol) (prepared as in the synthesis forcompound 57) 3,3-difluorocyclobutanamine hydrochloride (248.5 mg, 1.73mmol) DIPEA (0.6 mL, 3.46 mmol) in CH₃CN (22 mL) was stirred overnightat room temperature. The reaction mixture was concentrated. The residuewas subjected to column chromatography on silica using a gradient from10 till 100% EtOAc in heptane. The product fractions were partiallyconcentrated until product crystallized. The white crystals werefiltered off and dried overnight in vacuo at 50° C., resulting incompound 164 (175 mg) Method A: Rt: 1.86 min m/z: 438.0 (M−H)⁻ Exactmass: 439.04. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.36-2.58 (m, 2H),2.72-2.90 (m, 2H), 3.48-3.63 (m, 1H), 3.92 (s, 3H), 7.34 (d, J=1.8 Hz,1H), 7.63 (d, J=1.8 6 Hz, 1H), 7.75-7.88 (m, 3H), 10.29 (s, 1H)¹H NMR(400 MHz, ACETONITRILE-d₃) δ ppm 2.40-2.58 (m, 2H), 2.74-2.89 (m, 2H),3.59-3.72 (m, 1H), 3.93 (s, 3H), 5.84 (d, J=1.0 Hz, 1H), 7.13 3 (d,J=1.8 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.56-7.61 (m, 1H), 7.61-7.69 (m,1H), 8.63 (s, 1H).

Compound 165:N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[[1-methyl-1-(trifluoro-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1034 mg. 12 mmol) (prepared as in the synthesis for compound57) 1,1,1-trifluoro-2-methyl-butan-2-amine hydrochloride (754 mg, 4.25mmol) DIPEA (1.14 mL, 36.58 mmol) in CH₃CN (31 mL) was refluxed 2 days.The reaction mixture was concentrated. The residue was dissolved inEtOAc (100 mL), washed with 1M HCl, dried over sodium sulphate, filteredand concentrated. The residue was subjected to column chromatography onsilica using a gradient from 10 till 100% EtOAc in heptane. The productfractions were concentrated yielding compound 165 (300.1 mg) as a whitesolid. The racemic mixture 165 was separated in enantiomers 165a and165b by Prep SFC (Stationary phase: Chiralpak Diacel AD 20×250 mm),Mobile phase: CO₂, iPrOH with 0.2% iPrNH₂), the desired fractions werecollected, evaporated, dissolved in MeOH and evaporated again, yielding165a (first eluding, white solid, 45 mg). Method A: Rt: 2.10 min m/z:472.0 (M−H)⁻ Exact mass: 473.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79(t, J=7.3 Hz, 3H), 1.37 (s, 3H), 1.45-1.59 (m, 1H), 1.73-1.87 (m, 1H),3.92 (s, 3H), 7.34 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.76-7.86(m, 2H), 7.90 (s, 1H), 10.31 (s, 1H) and 165b (second eluding, 40 mg,white solid). Method A: Rt: 2.10 min m/z: 472.0 (M−H)⁻ Exact mass:473.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79 (t, J=7.3 Hz, 3H), 1.37 (s,3H), 1.46-1.59 (m, 1H), 1.74-1.87 (m, 1H), 3.92 (s, 3H), 7.34 (d, J=1.8Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.76-7.86 (m, 2H), 7.90 (s, 1H), 10.31(s, 1H).

Compound 166:N-(3-Chloro-4,5-difluorophenyl)-4-[(3,3-difluorocyclopentyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

A mixture of5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1496 mg. 3.07 mmol) (prepared as in the synthesis for compound57) 3,3-difluorocyclopentanamine (819 mg, 6.76 mmol) DIPEA (0.79 mL,4.61 mmol) in CH₃CN (23 mL) was refluxed 1 hour. The reaction mixturewas concentrated. The residue was dissolved in EtOAc (100 mL), washedwith 1M HCl, dried over sodium sulphate, filtered and concentrated. Theresidue was subjected to column chromatography on silica using agradient from 10 till 100% EtOAc in heptane. The product fractions werepartially concentrated until the product started to crystallize. Thewhite crystals were filtered off and dried overnight in vacuo at 50° C.,resulting in compound 166 (856.3 mg) Method A: Rt: 1.87 min m/z: 452.0(M−H)⁻ Exact mass: 453.05. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.75 (m,1H), 1.87-2.07 (m, 3H), 2.07-2.23 (m, 1H), 2.24-2.40 (m, 1H), 3.55-3.70(m, 1H), 3.92 (s, 3H), 7.34 (d, J=2.0 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H),7.65 (d, J=6.8 Hz, 1H), 7.77-7.86 (m, 2H), 10.31 (s, 1H) Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 198.05°C.

The racemic mixture 166 was was separated in enantiomers 166a and 166bby Prep SFC (Stationary phase: Chiralpak Diacel AD 20×250 mm), Mobilephase: CO₂, MeOH-iPrOH (50-50) with 0.2% iPrNH₂), the desired fractionswere collected, evaporated, dissolved in MeOH and evaporated again, Theresidues were dissolved in methanol (20 mL) and crystallized uponaddition of water. The white powders were filtered off and driedovernight in vacuo at 50° C., resulting in compound 166a (285.5 mg,first eluding enantiomer), 166b (296 mg, second eluding enantiomer)Method A: Rt: 1.96 min m/z: 452.0 (M−H)⁻ Exact mass: 453.05. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.58-1.73 (m, 1H), 1.88-2.07 (m, 3H), 2.07-2.23 (m,1H), 2.24-2.41 (m, 1H), 3.57-3.69 (m, 1H), 3.92 (s, 3H), 7.34 (d, J=1.8Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.65 (d, J=6.6 Hz, 1H), 7.75-7.87 (m,2H), 10.31 (s, 1H).

Compound 167:4-(Bicyclo[1.1.1]pent-1-ylsulfamoyl)-N-(3-chloro-4,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 167 was prepared similarly as described for compound 164 usingbicyclo[1.1.1]pentan-1-amine hydrochloride instead of3,3-difluorocyclobutanamine hydrochloride. The product fractions aftercolumn chromatography were concentrated and the residue dissolved in hotmethanol (25 mL). The product crystallized upon addition of a smallamount of water. The white powder was filtered off and dried overnightin vacuo at 50° C., resulting in compound 167 (226 mg) Method A: Rt:1.89 min m/z: 414.0 (M−H)⁻ 416.0 (M+H)⁺ Exact mass: 415.06. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.81 (s, 6H), 2.31 (s, 1H), 3.93 (s, 3H), 7.34 (d,J=2.0 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.77-7.86 (m, 2H), 8.22 (s, 1H),10.29 (s, 1H).

Compound 168:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-[(3,3,3-trifluoropropyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 168 was prepared similarly as described for compound 164 using3,3,3-trifluoropropylamine instead of 3,3-difluorocyclobutanaminehydrochloride but was stirred 3 hours at room temperature. Water wasadded until the product start to crystallize. The white powder wasfiltered off and dried overnight in vacuo at 50° C. Method A: Rt: 1.95min m/z: 444.0 (M−H)⁻ Exact mass: 445.03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.40-2.55 (m, 2H), 2.95-3.05 (m, 2H), 3.92 (s, 3H), 7.35 (d, J=2.0 Hz,1H), 7.52 (t, J=5.9 Hz, 1H), 7.65 (d, J=1.8 6 Hz, 1H), 7.76-7.86 (m,2H), 10.31 (s, 1H).

Compound 169:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-[(3,3,3-trifluoro-1-methylpropyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 169 was prepared similarly as compound 164 using4,4,4-trifluorobutan-2-amine hydrochloride instead of3,3-difluorocyclobutanamine hydrochloride. Water was added until theproduct starts to crystallize. The white powder was filtered off anddried overnight in vacuo at 50° C., resulting in compound 169 (542 mg).Method A: Rt: 1.91 min m/z: 458.0 (M−H)⁻ Exact mass: 459.04. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.8 Hz, 3H), 2.32-2.47 (m, 2H), 3.43-3.55(m, 1H), 3.92 (s, 3H), 7.34 (d, J=1.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H),7.62 (d, J=1.8 Hz, 1H), 7.76-7.86 (m, 2H), 10.30 (s, 1H). The racemiccompound 169 (492 mg) was separated in enantiomers 169a and 169b by PrepSFC (Stationary phase: Chiralpak Diacel AD 20×250 mm), Mobile phase:CO₂, MeOH with 0.2% iPrNH₂), the desired fractions were collected,evaporated, solved in MeOH and evaporated again. The residue wascrystallized from 25 mL methanol upon addition of water, filtered offand dried overnight in vacuo at 50° C. yielding white crystals,resulting in compound 169a (first eluding enantiomer, 144 mg) and 169b(second eluding enantiomer, 135 mg).

Compound 170:N-(3-Cyano-4-fluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (preparedsimilarly as described in the synthesis of3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid for compound 74, from5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid (heating 60minutes at 80° C. in thionylchloride instead of 30 minutes at 80° C.;4880 mg, 19.4 mmol) was dissolved in CH₃CN (50 mL), DIPEA (10.04 mL,58.27 mmol) was added followed by (2R)-1,1,1-trifluoropropan-2-amine(3295 mg, 29.14 mmol) and the mixture was refluxed for 3 hours. Thereaction mixture was concentrated. The residue was dissolved in EtOAc(200 mL), washed with water, dried over sodium sulphate, filtered andconcentrated. The residue was purified by column chromatography onsilica using a gradient from 5 till 100% EtOAc in heptane. The productfractions were concentrated in vacuo yielding ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylateas a light brown semisolid which was used as such (1705 mg). Method A:Rt 1.68 min, m/z: 345 (M−H)⁻ 347.0 (M+H)⁺ Exact mass: 346.06. A mixtureof ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1705 mg, 4.92 mmol), LiOH (354 mg, 14.77 mmol) THF (17 mL) and water (4mL) was stirred overnight. The reaction mixture was concentrated, theresidue dissolved in water (50 mL) and the solution was neutralised withHCl 1M (14.77 mL, 14.77 mmol). The mixture was extracted with Me-THF(2×100 mL). The organic layer was dried over sodium sulphate, filteredand concentrated resulting in3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (1533 mg) as a powder, which was used as such. Method A: Rt: 0.88m/z: 317 (M−H)⁻ Exact mass: 318.03. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15(d, J=7.0 Hz, 3H), 3.82 (s, 3H), 3.88-4.04 (m, 1H), 7.56 (d, J=4.8 Hz,1H), 8.56 (d, J=8.8 Hz, 1H), 13.13 (br. s., 1H). Compound 170 (531 mg)was synthesized similarly as described for compound 94 using3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (601.7 mg 1.89 mmol) instead of3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid and 5-amino-2-fluorobenzonitrile (531 mg, 3.78 mmol) instead of4-fluoro-3-methylaniline and the reaction mixture was stirred overnightat 65° C. The column fractions were concentrated and the residue wascrystallized by dissolving in 100 mL warm methanol upon addition ofwater. The crystals were filtered off and dried overnight in vacuo at50° C. Method A: Rt: 1.66 min m/z: 435 (M−H)⁻ Exact mass: 436.06. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.8 Hz, 3H), 3.81 (s, 3H), 3.91-4.05(m, 1H), 7.50-7.59 (m, 2H), 7.96 (ddd, J=9.2, 5.0, 2.8 Hz, 1H), 8.17(dd, J=5.8, 2.8 Hz, 1H), 8.62 (d, J=8.8 Hz, 1H), 10.36 (s, 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 190.99° C.

Alternative Synthesis of Compound 170:

Sodium hydride (6.99 g, 183 mmol) was added portionwise to ethyl3-fluoropyrrole-2-carboxylate (23.9 g, 152 mmol), iodomethane (25.9 g,183 mmol) in DMF (238 mL) under nitrogen in an icebath and stirredovernight at room temperature. The reaction mixture was acidified with1M HCl and concentrated. The residue was dissolved in water/EtOAc. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained residue was dissolved in CH₃CN (150 mL), washed with heptaneand concentrated at 60° C. and 40 mbar yielding a brown liquid which wassubmitted to silica gel column chromatography using a gradient from 10to 25% EtOAc in heptane. The product fractions were concentratedresulting in ethyl 3-fluoro-1-methyl-pyrrole-2-carboxylate as a clearoil (14.0 g). Chlorosulfonic acid (9.97 g, 85.6 mmol) dissolved indichloromethane (50 mL) was added to ethyl3-fluoro-1-methyl-pyrrole-2-carboxylate (14.0 g, 81.5 mmol) dissolved indichloromethane (250 mL) in an icebath and stirred 30 minutes. Theformed light beige crystals were filtered off and dried overnight invacuo at 50° C., resulting in5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid (14.3 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.2 Hz, 3H), 3.72 (s, 3H), 4.23(q, J=7.0 Hz, 2H), 7.02 (d, J=5.1 Hz, 1H). Method D: Rt: 0.88 min. m/z:250.0 (M−H)⁻ Exact mass: 251.0.5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid (20.3 g, 80.7mmol) in SOCl₂ (80 mL, 1.1 mol) was stirred 2 hours at 80° C. Thereaction mixture was concentrated. The obtained dark green solid wassubjected to silica gel column chromatography using a gradient from 10to 50% EtOAc in heptane. The product fractions were concentratedyielding ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate(18.9 g) as light yellow crystals which was used as such. Ethyl4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (18.9 g, 70.1mmol) (2R)-1,1,1-trifluoropropan-2-amine (11.89 g, 105.2 mmol) NaHCO₃(17.7 g, 210 mmol) in acetonitrile (150 mL) with molecular sieves 4A (15g) and was refluxed overnight. The reaction mixture was filtered andconcentrated. The residue was dissolved in EtOAc and washed with 1 MHCl. The organic layer was dried over sodium sulphate, filtered andconcentrated. The residue was purified via silica gel columnchromatography (2×) using a gradient from 10 to 100% EtOAc in heptane,resulting in ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylateas a white powder which was dried overnight at 50° C. in vacuo (19.1 gin total). Method D: Rt: 1.77 min. m/z: 345.0 (M−H)⁻ Exact mass: 346.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=7.0 Hz, 3H), 1.28 (t, J=7.2Hz, 3H), 3.83 (s, 3H), 3.90-4.03 (m, 1H), 4.28 (q, J=7.2 Hz, 2H), 7.60(d, J=4.8 Hz, 1H), 8.60 (d, J=8.8 Hz, 1H). To ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(10.0 g, 28.9 mmol) and 5-amino-2-fluoro-benzonitrile (5.11 g, 37.6mmol)) dissolved in dry THF (200 mL) at 5° C. under nitrogen atmosphere,lithium bis(trimethylsilyl)amide in toluene (115.6 mL, 1 M, 115.6 mmol)was added. The mixture was stirred 4 hours allowing to reach roomtemperature. The reaction mixture was quenched with NH₄Cl (250 mL)solution and extracted with EtOAc (500 mL), diluted with brine (200 mL)and extracted again with EtOAc (300 mL). The combined organic layerswere dried over sodium sulphate, filtered and concentrated. The residuewas purified by silica gel column chromatography with a gradient from 10to 100% EtOAc in heptane. The product fractions were concentrated andthe solid residue was crystallised from warm methanol (300 mL) uponaddition of water. The pink crystals were filtered off and dried invacuo at 50° C. overnight. The compound was repeatedly purified bysilica gel chromatography (using 10 to 100% EtOAc in heptane and usingdichloromethane). The resulting product was crystallised once more fromhot methanol (500 mL) and the product crystallised upon addition ofwater. The white powder was filtered off and dried overnight in vacuo at50° C., resulting in compound 170 (9.28 g). Method D: Rt: 1.86 min m/z:435.3 (M−H)⁻ Exact mass: 436.1. Differential scanning calorimetry: From30 to 300° C. at 10° C./min: peak at 192.2° C. [α]₅₈₉ ²⁰=−23.2° (c 0.504w/v %, DMF).

Compound 171:N-(3-Cyano-4-fluorophenyl)-3-fluoro-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Intermediate ethyl3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylate was madesimilarly as described for ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylatestarting from 5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid(1220 mg, 4.86 mmol), converting it to the sulphonyl chloride withthionyl chloride (heating at 80° C. during 1 hour) and reaction withisopropylamine (1160 mg, 19.42 mmol) resulting in ethyl3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1169 mg)as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.6 Hz,6H), 1.28 (t, J=7.2 Hz, 3H), 3.26-3.37 (m, 1H), 3.82 (s, 3H), 4.27 (q,J=7.2 Hz, 2H), 7.52 (d, J=4.6 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H) Method A:Rt: 1.48 min m/z: 291 (M−H)⁻ Exact mass: 292.09. Intermediate3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid wasmade similarly as for compound 170 using ethyl3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1169 mg,4.0 mmol) The reaction mixture was concentrated. The residue wasdissolved in water (75 mL) and neutralised with HCl 1M (12.0 mL, 12.0mmol). The product crystallized and was filtered off. The white powderwas dried overnight in vacuo at 50° C., resulting in3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (856mg) Method A: Rt: 0.75 min m/z: 263.0 (M−H)⁻ Exact mass: 264.06. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.6 Hz, 6H), 3.22-3.38 (m, 1H), 3.81(s, 3H), 7.47 (d, J=4.8 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 13.06 (s, 1H).Compound 171 was made similarly as compound 170 using3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (594mg, 2.25 mmol) resulting in compound 171 (670 mg) as a white powder.Method A: Rt: 1.59 min m/z: 381 (M−H)⁻ Exact mass: 382.09. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.05 (d, J=6.6 Hz, 6H), 3.26-3.42 (m, 1H), 3.80 (s,3H), 7.48 (d, J=4.6 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.59 (d, J=7.3 Hz,1H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.17 (dd, J=5.8, 2.8 Hz, 1H),10.32 (s, 1H) Differential scanning calorimetry: From 30 to 300° C. at10° C./min: peak at 204.47° C.

Compound 172:N-(3-Chloro-2,4-difluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (250 mg, 1.02mmol was dissolved in CH₃CN (15 mL). Triethylamine (0.56 mL),3-chloro-2,4-difluoroaniline (183 mg, 1.12 mmol) and HATU (463 mg, 1.22mmol) were added. The reaction mixture was stirred at room temperaturefor 1 h, next at 50° C. for 80 h and then for 24 h at 75° C. Thesolution was allowed to cool down. The solvent was evaporated leaving ayellow oil which was dissolved in CH₂Cl₂/MeOH (2 mL, 95:5) and purifiedby Flash Chromatography on silica using a gradient of EtOAc-heptane0/100 to 100/0]. The desired fractions were combined and the solvent wasevaporated leaving a brown stable foam which was dissolved in a boilingmixture of of diisopropyl ether (3 mL) and CH₃CN (0.5 mL). The solutionwas allowed to cool while stirring. The precipitate was filtered off,washed once with its own filtrate and with of diisopropyl ether (2 mL).The product was collected as a white solid and dried in vacuo at 50° C.,resulting in compound 172 (60 mg). Method B: Rt: 0.98 min m/z: 390.1(M−H)⁻ Exact mass: 391.06. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.02 (d,J=6.6 Hz, 6H), 3.26 (dd, J=13.4, 6.8 Hz, 1H), 3.89 (s, 3H), 7.25 (d,J=6.6 Hz, 1H), 7.28-7.39 (m, 2H), 7.48-7.59 (m, 2H), 10.16 (s, 1H).

Compound 173:N-(3-Chloro-2-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (0.75 g, 3.05mmol) was dissolved in N,N-dimethylformamide (2 mL). HATU (1.27 g, 3.35mmol) was added and the mixture was stirred for 20 minutes. DIPEA (1.31mL, 7.61 mmol) was added followed by 3-chloro-2-fluoroaniline (0.44 g,3.05 mmol). The reaction mixture was stirred at 50° C. for 16 hours.Then this mixture was purified by silica gel column chromatography usinggradient elution from heptane to EtOAc. (100:0 to 0:100). The desiredfractions were concentrated in vacuo and the obtained residue wascrystallized out of MeOH/water. The precipitate was collected on a glassfilter and dried in a vacuum oven at 55° C. for 24 hours yieldingcompound 173 (477 mg) as a white powder. Method B: Rt: 0.97 min m/z:372.1 (M−H)⁻ Exact mass: 373.07. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03(d, J=6.6 Hz, 6H), 3.21-3.30 (m, 1H), 3.90 (s, 3H), 7.18-7.27 (m, 2H),7.32 (d, J=1.8 Hz, 1H), 7.44 (ddd, J=8.2, 6.8, 1.5 Hz, 1H), 7.50 (ddd,J=8.1, 6.8, 1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 10.12 (s, 1H).

Compound 174:N-(3-Chloro-4-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 174 (681 mg) was prepared similarly as described for compound173 using 3-chloro-4-fluoroaniline (0.44 g, 3.05 mmol) instead of3-chloro-2-fluoroaniline resulting in a white powder. Method B: Rt: 1.02min m/z: 372.1 (M−H)⁻ Exact mass: 373.07. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.02 (d, J=6.6 Hz, 6H), 3.19-3.29 (m, 1H), 3.92 (s, 3H), 7.20 (br.s., 1H), 7.32 (d, J=1.8 Hz, 1H), 7.39 (t, J=9.1 Hz, 1H), 7.55 (d, J=1.8Hz, 1H), 7.66 (ddd, J=9.0, 4.2, 2.6 Hz, 1H), 8.02 (dd, J=6.8, 2.6 Hz, 1H10.22 (br. s., 1H).

Compound 175:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 175 (576 mg) was prepared similarly as described for compound173 using 5-amino-2-fluorobenzonitrile (0.41 g, 3.05 mmol) instead of3-chloro-2-fluoroaniline resulting in a white powder. Method B: Rt: 0.91min m/z: 363.2 (M−H)⁻ Exact mass: 364.10. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.02 (d, J=6.6 Hz, 6H), 3.18-3.29 (m, 1H), 3.92 (s, 3H), 7.22 (d,J=5.5 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.49-7.56 (m, 1H), 7.57 (d, J=1.8Hz, 1H), 7.89-8.10 (m, 1H), 8.15-8.27 (m, 1H), 10.37 (br. s., 1H).

Compound 176:N-(3-Cyano-2-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 176 (294 mg) was prepared similarly as described for compound173 using 3-cyano-2-fluoroaniline (0.41 g, 3.05 mmol) instead of3-chloro-2-fluoroaniline resulting in a white powder. Method B: Rt: 0.85min m/z: 363.1 (M−H)⁻ Exact mass: 364.10. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.03 (d, J=6.4 Hz, 6H), 3.18-3.30 (m, 1H), 3.79-3.97 (m, 3H), 7.22(d, J=6.8 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.37-7.48 (m, 1H), 7.57 (d,J=1.8 Hz, 1H), 7.71-7.81 (m, 1H), 7.83-7.98 (m, 1H), 10.25 (br. s., 1H).

Compound 177:N-(3-Cyanophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 177 (629 mg) was prepared similarly as described for compound173 using 3-aminobenzonitrile (0.36 g, 3.05 mmol) instead of3-chloro-2-fluoroaniline resulting in a white powder. Method A: Rt: 1.49min m/z: 345.1 (M−H)⁻ Exact mass: 346.11. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.02 (d, J=6.6 Hz, 6H), 3.20-3.30 (m, 1H), 3.93 (s, 3H), 7.21 (br.s., 1H), 7.36 (d, J=1.8 Hz, 1H), 7.48-7.61 (m, 3H), 7.94-8.04 (m, 1H),8.11-8.26 (m, 1H), 10.34 (br. s., 1H).

Compound 178:N-(3-Cyano-2,4-difluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 178 (244 mg) was was prepared similarly as described forcompound 173 using 3-amino-2,6-difluorobenzonitrile (0.47 g, 3.05 mmol)instead of 3-chloro-2-fluoroaniline resulting in a white powder. MethodB: Rt: 0.89 min m/z: 381.1 (M−H)⁻ Exact mass: 382.09. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.03 (d, J=6.6 Hz, 6H), 3.20-3.29 (m, 1H), 3.90 (s, 3H),7.22 (d, J=6.8 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 7.45 (td, J=8.9, 1.5 Hz,1H), 7.56 (d, J=1.8 Hz, 1H), 7.94 (td, J=8.9, 6.2 Hz, 1H), 10.25 (br.s., 1H).

Compound 179:N-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 179 was was prepared similarly as described for compound 144using 3-methyl-3-oxetanamine (2.29 g, 26.3 mmol) instead of(R)-1,1,1-trifluoro-2-propylamine in Step 2 and, in step 4,1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid(155 mg, 0.54 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.2 g, 1.08mmol) and HATU (0.25 g, 0.65 mmol) were dissolved in DMF (0.72 mL)containing DIPEA (0.23 mL, 1.34 mmol). The reaction mixture was stirredat 40° C. for 42 hours and allowed to reach room temperature. Thereaction mixture was purified using silica gel column chromatography(ethyl acetate in heptane from 10 to 70%). The desired fractions werecombined and evaporated to afford light yellow oil. The yellow oil waspurified using silica gel column chromatography (ethyl acetate inheptane from 40 to 70%) yielding compound 179 (93 mg) as white powderwhich was dried in vacuum oven at 50° C. Method B: Rt: 0.97 min m/z:448.1 (M−H)⁻ Exact mass: 449.10. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54(s, 3H), 2.34 (s, 3H), 3.73 (s, 3H), 4.13 (d, J=6.4 Hz, 2H), 4.63 (d,J=5.9 Hz, 2H), 7.48 (s, 1H), 7.52 (t, J=9.8 Hz, 1H), 7.89-8.00 (m, 2H),8.20 (dd, J=6.6, 2.6 Hz, 1H), 10.42 (br. s., 1H).

Compound 180:N-(3-Cyanophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 180 was prepared similarly as described for compound 170 using3-aminobenzonitrile (138 mg, 1.16 mmol) instead of5-amino-2-fluorobenzonitrile. The column fractions were concentrated andthe residue was crystallized by dissolving in 10 mL warm methanol uponaddition of water. The crystals were filtered off and dried overnight invacuo at 50° C. resulting in a white powder (121 mg). Method A: Rt: 1.72min m/z: 417.0 (M−H)⁻ Exact mass: 418.07. ¹H NMR (360 MHz, DMSO-d₆) δppm 1.18 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.91-4.05 (m, 1H), 7.54-7.61(m, 3H), 7.89-7.96 (m, 1H), 8.14 (d, J=1.1 Hz, 1H), 8.64 (d, J=8.4 Hz,1H), 10.40 (s, 1H).

Compound 181:N-(3-Cyano-2,4-difluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 181 was prepared similarly as described for compound 180 using3-amino-2,6-difluorobenzonitrile (143 mg, 0.928 mmol) instead of3-aminobenzonitrile resulting in a white powder (79 mg). Method A: Rt:1.77 min m/z: 453.0 (M−H)⁻ Exact mass: 454.05. ¹H NMR (360 MHz, DMSO-d₆)δ ppm 1.18 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.92-4.04 (m, 1H), 7.43-7.51(m, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.98-8.08 (m, 1H), 8.66 (d, J=8.8 Hz,1H), 10.06 (s, 1H).

Compound 182:N-(3-Cyano-2-fluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 182 was prepared similarly as described for compound 180 using3-amino-2-fluorobenzonitrile (127.5 mg, 0.936 mmol) instead of3-aminobenzonitrile resulting in a white powder (66 mg). Method A: Rt:1.78 min m/z: 435.1 (M−H)⁻ Exact mass: 436.06. ¹H NMR (360 MHz, DMSO-d₆)δ ppm 1.18 (d, J=7.0 Hz, 3H), 3.82 (s, 3H), 3.91-4.06 (m, 1H), 7.43 (t,J=7.7 Hz, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.78 (ddd, J=7.8, 5.9, 1.6 Hz,1H), 8.03 (td, J=8.0, 1.6 Hz, 1H), 8.66 (d, J=8.8 Hz, 1H), 10.06 (s,1H).

Compound 183:3-Fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-N-(2,3,4-trifluorophenyl)-1H-pyrrole-2-carboxamide

Compound 183 was prepared similarly as described for compound 180 using2,3,4-trifluoroaniline (136.8 mg, 0.911 mmol) instead of3-aminobenzonitrile resulting in a white powder (79 mg). Method A: Rt:1.89 min m/z: 446.0 (M−H)⁻ Exact mass: 447.05. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.19 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.91-4.04 (m, 1H), 7.29-7.39(m, 1H), 7.42-7.50 (m, 1H), 7.56 (d, J=4.6 Hz, 1H), 8.61 (d, J=8.8 Hz,1H), 9.93 (s, 1H).

Compound 184:N-(3-Bromo-2,4-difluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 184 was prepared similarly as described for compound 180 using3-bromo-2,4-difluoroaniline (194.9 mg, 0.937 mmol) instead of3-aminobenzene resulting in a white powder (115 mg). Method A: Rt: 1.98min m/z: 508.0 (M−H)⁻ Exact mass: 506.97. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.19 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.90-4.04 (m, 1H), 7.27-7.35(m, 1H), 7.56 (d, J=4.4 Hz, 1H), 7.64-7.73 (m, 1H), 8.61 (d, J=8.8 Hz,1H), 9.86 (s, 1H).

Compound 185:N-(3-Chloro-2,4-difluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 185 was prepared similarly as described for 180 using3-chloro-2,4-difluoroaniline (150.9 mg, 0.923 mmol) instead of3-aminobenzene resulting in a white powder (115 mg). Method A: Rt: 1.97min m/z: 462.0 (M−H)⁻ Exact mass: 463.02. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.19 (d, J=6.8 Hz, 3H), 3.81 (s, 3H), 3.92-4.04 (m, 1H), 7.35 (td,J=8.9, 2.0 Hz, 1H), 7.56 (d, J=4.6 Hz, 1H), 7.65 (td, J=8.7, 5.8 Hz,1H), 8.61 (d, J=8.6 Hz, 1H), 9.88 (s, 1H).

Compound 186:N-(3-Cyano-4-fluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-1-methyl-propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Intermediate ethyl3-fluoro-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxylatewas made similarly as described for compound 170 using5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrole-3-sulfonic acid (541.4 mg,2.155 mmol), converting it to the corresponding sulphonylchloride withthionylchloride (heating at 80° C. during 90′) and reacting this with(R)-(−)-2-aminobutane (238.8 mg, 3.233 mmol) resulting in ethyl3-fluoro-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxylate(354 mg) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76 (t,J=7.4 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.31-1.40(m, 2H), 3.01-3.18 (m, 1H), 3.81 (s, 3H), 4.27 (q, J=7.2 Hz, 2H),7.47-7.57 (m, 2H). To ethyl3-fluoro-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxylate(354 mg, 1.156 mmol) and 5-amino-2-fluoro-benzonitrile (201.7 mg, 1.483mmol) in dry THF (20 mL) at 0° C., lithium bis(trimethylsilyl)amide inTHF (4.62 mL, 4.62 mmol) was added. The mixture was stirred 1 hour at 0°C. The reaction mixture was quenched with NH₄Cl solution (30 mL) andextracted with EtOAc (50 mL), diluted with brine (50 mL) and extractedagain with EtOAc (50 mL). The combine organic layers were dried oversodium sulphate, filtered and concentrated. The residue (dissolved in 1mL DMF) was purified by column chromatography on silica using a gradientfrom 10 till 100% EtOAc in heptane. The product fractions wereconcentrated and the solid residue was crystallized from 50 mL warmmethanol upon addition of water. The white crystals were filtered offand dried in vacuo at 50° C. overnight, resulting in compound 186 (306mg) Method A: Rt: 1.83 min m/z: 395.1 (M−H)⁻ Exact mass: 396.11. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.78 (t, J=7.4 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H),1.31-1.44 (m, 2H), 3.06-3.20 (m, 1H), 3.80 (s, 3H), 7.47 (d, J=4.6 Hz,1H), 7.50-7.58 (m, 2H), 7.96 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.17 (dd,J=5.7, 2.6 Hz, 1H), 10.31 (s, 1H).

Compound 187:N-(3-Cyano-4-fluorophenyl)-4-[(3,3-difluoro-1-methylcyclobutyl)sulfamoyl]-3-fluoro-1-methyl-1H-pyrrole-2-carboxamide

Compound 187 (290 mg) was prepared similarly as described for compound186 using 3,3-difluoro-1-methyl-cyclobutanamine hydrochloride (509.4 mg,3.232 mmol) instead of (R)-(−)-2-aminobutane resulting in a whitepowder. Method A: Rt: 1.84 min m/z: 443.1 (M−H)⁻ Exact mass: 444.09. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 3H), 2.47-2.62 (m, 2H), 2.80-2.97(m, 2H), 3.81 (s, 3H), 7.49-7.58 (m, 2H), 7.96 (ddd, J=9.2, 5.0, 2.8 Hz,1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H), 8.22 (s, 1H), 10.33 (s, 1H).

Compound 188:N-(3-Cyano-4-fluorophenyl)-3-fluoro-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 188 (409 mg) was prepared similarly as described for compound186 using (2S)-1,1,1-trifluoropropan-2-amine instead of(R)-(−)-2-aminobutane resulting in a white powder. Method A: Rt: 1.89min m/z: 435.0 (M−H)⁻ Exact mass: 436.06. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.18 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.92-4.05 (m, 1H), 7.50-7.59(m, 2H), 7.96 (ddd, J=9.2, 4.9, 2.9 Hz, 1H), 8.17 (dd, J=5.7, 2.6 Hz,1H), 8.62 (d, J=8.8 Hz, 1H), 10.36 (s, 1H). Differential scanningcalorimetry: peak at 190.92° C.

Compound 189:N-(3-Chloro-4,5-difluorophenyl)-1-methyl-4-{[1-(trifluoromethyl)-cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (470.2 mg, 0.966 mmol) 1-trifluoromethyl)cyclobutan-1-amine(268.7 mg, 1.932 mmol DIPEA (0.518 mL, 2.99 mmol) was dissolved in CH₃CNand refluxed over weekend. The reaction mixture was concentrated. Theresidue was dissolved in EtOAc (100 mL), washed with 1M HCl, dried oversodium sulphate, filtered and concentrated. The residue was purified bycolumn chromatography on a silica using a gradient from 10 till 100%EtOAc in heptane. The product fractions were concentrated yielding abeige powder. This powder was repurified by Prep HPLC (Stationary phase:RP XBridge Prep C18 OBD-10 m, 30×150 mm), Mobile phase: 0.25% NH₄HCO₃solution in water, CH₃CN), yielding a white powder which was dried invacuo at 50° C., resulting in compound 189 (32.9 mg). Method B: Rt: 1.18min m/z: 470.0 (M−H)⁻ Exact mass: 471.04. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.71-1.87 (m, 2H), 2.24-2.36 (m, 2H), 2.39-2.48 (m, 2H), 3.93 (s,3H), 7.37 (d, J=2.0 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.76-7.87 (m, 2H),8.37 (s, 1H), 10.33 (s, 1H).

Compound 190:4-(tert-Butylsulfamoyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

methyl 4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5 g, 1.04 mmol)was dissolved in acetonitrile (100 mL). To this was addeddiisopropylethylamine (9.06 mL, 52.6 mmol) followed by Tert-Butylamine(3.23 g, 44.2 mmol) and the resulting mixture was refluxed for 2 hours.Then the mixture was cooled to room temperature and concentrated invacuo. The resulting residue was dissolved in dichloromethane (250 mL)and was washed with HCl (2×150 mL). The organics were dried on sodiumsulphate, filtered and concentrated in vacuo yielding a powder of methyl4-(tert-butylsulfamoyl)-1-methyl-pyrrole-2-carboxylate which was used assuch. (6.07 g) Method B: Rt: 1.52 min m/z: 273.0 (M−H)⁻ Exact mass:274.10. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.13 (s, 9H), 3.77 (s, 3H), 3.88(s, 3H) 7.00 (d, J=1.8 Hz, 1H), 7.18 (s, 1H), 7.60 (d, J=2.2 Hz, 1H).methyl 4-(tert-butylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (11.269 g,41.077 mmol) was dissolved in THF (120 mL). To this was added lithiumhydroxide (1.476 g, 1.5 eq) in distilled water (16 mL) and a turbidmixture was obtained. Then MeOH (6 mL) was added and the mixture becameclear. The resulting mixture was stirred for 18 hours. Then it wasconcentrated until water remained and distilled water (30 mL) was added.The mixture was neutralized using an exact amount of hydrochloric acid(1M/aq/61.6 mL, 61.62 mmol). The resulting mixture was extracted using2-methyltetrahydrofuran. The combined extracts were dried on MgSO₄,filtered and concentrated under reduced pressure resulting in4-(tert-butylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid as a whitepowder which was used without further purifications for the next step(10.62 g). Method B: Rt: 0.83 min m/z: 258.9 (M−H)⁻ Exact mass: 260.08.Compound 190 (2140 mg) was prepared similarly as described for compound158 using 5-amino-2-fluorobenzonitrile (1348 mg, 9.604 mmol) and4-(tert-butylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid and stirringat 50° C. instead of room temperature, resulting in a white solid.Method B: Rt: 0.96 min m/z: 377.1 (M−H)⁻ Exact mass: 378.12. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (s, 9H) 3.91 (s, 3H) 7.14 (s, 1H) 7.34 (d,J=1.76 Hz, 1H) 7.48-7.56 (m, 2H) 7.98-8.05 (m, 1H) 8.22 (dd, J=5.83,2.75 Hz, 1H) 10.34 (s, 1H).

Compound 191:4-(tert-Butylsulfamoyl)-N-(3-cyanophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 191 (758 mg) was prepared similarly as described for compound190 using 3-aminobenzonitrile (458.4 mg, 3.84 mmol) instead of5-amino-2-fluorobenzonitrile resulting in a white solid. Method B: Rt:0.92 min m/z: 359.1 (M−H)⁻ Exact mass: 360.13. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.18 (s, 9H) 3.92 (s, 3H) 7.13 (s, 1H) 7.36 (s, 1H) 7.51-7.59 (m,3H) 7.99 (d, J=7.04 Hz, 1H) 8.19 (s, 1H) 10.31 (s, 1H).

Compound 192:4-(tert-Butylsulfamoyl)-N-(3-cyano-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 192 (733 mg) was prepared similarly as described for compound190 using 3-amino-2-fluorobenzonitrile (522.9 mg, 3.842 mmol) instead of5-amino-2-fluorobenzonitrile resulting in a white solid. Method B: Rt:0.90 min m/z: 377.1 (M−H)⁻ Exact mass: 378.12. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.18 (s, 9H) 3.89 (s, 3H) 7.15 (s, 1H) 7.34 (d, J=2.0 Hz, 1H) 7.42(t, J=7.9 Hz, 1H) 7.55 (d, J=1.76 Hz, 1H) 7.77 (ddd, J=7.7, 5.9, 1.8 Hz,1H) 7.90 (td, J=7.90, 1.5 Hz, 1H) 10.23 (s, 1H).

Compound 193:4-(tert-Butylsulfamoyl)-N-(3-chloro-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 193 (787 mg) was prepared similarly as described compound 190using 3-chloro-2-fluoroaniline (0.435 mL, 3.84 mmol) resulting in awhite solid. Method B: Rt: 1.02 min m/z: 386.1 (M−H)⁻ Exact mass:387.08. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H) 3.89 (s, 3H) 7.14(s, 1H) 7.20-7.26 (m, 1H) 7.32 (d, J=1.76 Hz, 1H) 7.41-7.46 (m, 1H)7.48-7.54 (m, 2H) 10.10 (s, 1H).

Compound 194:4-(tert-Butylsulfamoyl)-N-(3-chloro-2,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 194 (708 mg) was prepared similarly as described for compound190 using 3-chloro-2,4-difluoroaniline (628.3, 3.84 mmol) resulting in awhite solid. Method B: Rt: 1.03 min m/z: 404.1 (M−H)⁻ Exact mass:405.07. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H) 3.89 (s, 3H) 7.15(s, 1H) 7.30-7.37 (m, 2H) 7.48-7.58 (m, 2H) 10.11 (s, 1H).

Compound 195:4-(tert-Butylsulfamoyl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 195 (705 mg) was prepared similarly as described for compound190 using 3-chloro-4-fluoroaniline (559.2 mg, 3.842 mmol) resulting in awhite solid. Method A: Rt: 1.95 min m/z: 386.0 (M−H)⁻ Exact mass:387.08. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H), 3.91 (s, 3H), 7.12(s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.39 (t, J=9.1 Hz, 1H), 7.53 (d, J=1.8Hz, 1H), 7.63-7.70 (m, 1H), 8.02 (dd, J=6.8, 2.6 Hz, 1H), 10.19 (s, 1H).

Compound 196:N-(3-Cyano-2,4-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Methyl1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(0.7 g, 2.23 mmol) was dissolved in THF (10 mL) under nitrogen. To thiswas added 3-amino-2,6-difluorobenzonitrile (0.45 g, 2.9 mmol) and themixture was cooled in an ice-water bath while stirred under nitrogen. Tothis was added drop wise lithium bis(trimethylsilyl)amide 1M in toluene(6.68 mL, 6.68 mmol) over a period of 10 minutes. The resulting mixturewas stirred for 1 hour while cooling was continued. The mixture wasquenched with saturated ammonium chloride (25 mL) and the resultingmixture was extracted using EtOAc (3×25 mL). The combined extracts werewashed with brine (20 mL), dried on Na₂SO₄, filtered and concentrated invacuo. The obtained residue was dissolved in 2 mL dichloromethane andthis was loaded on a dry silica plug. This was purified by columnchromatography using gradient elution from heptane to EtOAc. (100:0 to0:100). The desired fractions were collected and concentrated in vacuoyielding a powder. This powder was recrystallized out of MeOH/water. Theobtained crystals were collected on a filter, rinsed with water followedby diisopropylether and dried in a vacuo at 55° C. for 24 hoursresulting inN-(3-Cyano-2,4-difluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide(563 mg) as a powder. Method A: Rt: 1.75 min m/z: 435.0 (M−H)⁻ Exactmass: 436.06. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J=6.8 Hz, 3H),3.80-4.06 (m, 4H), 7.36 (d, J=2.0 Hz, 1H), 7.40-7.51 (m, 1H), 7.66 (d,J=1.5 Hz, 1H), 7.85-8.02 (m, 1H), 8.54 (br. s, 1H), 10.14 (br. s, 1H).

Compound 197:N-(3-Cyanophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]-sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 197 (697.6 mg) was prepared similarly as described for compound196 using 3-aminobenzonitrile (342 mg, 2.895 mmol) instead of3-amino-2,6-difluorobenzonitrile resulting inN-(3-cyanophenyl)-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamideas a solid. Method B: Rt: 0.93 min m/z: 399.1 (M−H)⁻ Exact mass: 400.08.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.8 Hz, 3H) 3.93 (s, 4H) 7.39(d, J=1.9 Hz, 1H) 7.52-7.60 (m, 2H) 7.65 (d, J=1.9 Hz, 1H) 7.99 (dt,J=6.9, 2.3 Hz, 1H) 8.20 (br. s, 1H) 8.17-8.20 (m, 1H) 10.35 (br. s.,1H).

Compound 198:N-(3-Cyano-2-fluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 198 (691 mg) was prepared similarly as described for compound196 using 3-amino-2-fluoro-benzonitrile (394 mg, 2.895 mmol) instead of3-amino-2,6-difluorobenzonitrile resulting in as a solid. Method B: Rt:0.91 min m/z: 417.1 (M−H)⁻ Exact mass: 418.07. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.03-1.18 (m, 3H), 3.84-4.03 (m, 4H), 7.38 (d, J=2.0 Hz, 1H), 7.42(t, J=7.9 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.77 (ddd, J=7.6, 6.0, 1.5Hz, 1H), 7.91 (td, J=7.8, 1.5 Hz, 1H), 7.99-9.14 (m, 1H), 10.26 (br. s.,1H).

Compound 199:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Sodium hydride (3.46 g, 90.2 mmol, 60% dispersion in oil) was addedportion wise, over a period of 10 minutes, to a solution of methyl3-chloro-1H-pyrrole-2-carboxylate (12 g, 75.2 mmol), iodomethane (12.8g, 90.2 mmol) and DMF (120 mL) at 0° C. under nitrogen in an ice bath.The ice bath was removed and the reaction mixture was stirred 3 hours atroom temperature. The reaction mixture was acidified with aqueoushydrochloric acid (15.04 mL, 1 M) and concentrated. The residue wasdissolved in water (100 mL)/ethyl acetate (300 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in acetonitrile (150 mL), washed with heptane (100 mL) andconcentrated at 70° C. yielding methyl3-chloro-1-methyl-pyrrole-2-carboxylate (12.0 g) as yellow liquid whichwas used as such. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.87 (s, 3H),3.88 (s, 3H), 6.13 (d, J=2.9 Hz, 1H), 6.69 (d, J=2.9 Hz, 1H) Methyl3-chloro-1-methyl-pyrrole-2-carboxylate (5.0 g, 25.1 mmol) was addeddrop wise to chlorosulfonic acid (11 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was warmed to room temperature andallowed to stir 2 hours. The resulting mixture was added drop wise to astirred, temperature controlled ice-water mixture (200 mL) keeping thetemperature under 5° C. A white precipitation was formed. The obtainedaqueous suspension was extracted using dichloromethane (3×100 mL). Thecombined organic extracts were washed with Brine and dried on sodiumsulphate, filtered and concentrated in vacuo yielding methyl3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5.56 g) aslight green powder which was used as such. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 3.94 (s, 3H), 3.98 (s, 3H), 7.46 (s, 1H). In amicrowave tube methyl3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.5 g, 5.51mmol) was dissolved in acetonitrile (10 mL). To this was added DIPEA(1.42 mL, 0.75 g/mL, 8.27 mmol) followed by(R)-1,1,1-trifluoro-2-propylamine (0.94 g, 8.27 mmol) and molecularsieves and the tube was closed and resulting mixture was heated at 80°C. 30 minutes under microwave irradiation. The reaction mixture wasconcentrated and the resulting brown sticky oil was dissolved indichloromethane (50 mL) and this was washed with HCl (1N, 2×10 mL) andBrine (5 mL) and dried on sodium sulphate. The solids were filtered offand the filtrate was concentrated in vacuo yielding brown oil. The brownoil was purified using silica gel column chromatography (ethyl acetatein heptane from 0 to 100%) to afford methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(660 mg) as white powder which was used as such. Method B: Rt: 0.88 minm/z: 347 (M−H)⁻ Exact mass: 348.02. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15(d, J=7.0 Hz, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 3.89-4.02 (m, 1H), 7.76(s, 1H), 8.51 (d, J=8.8 Hz, 1H). Methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(660 mg, 1.89 mmol) and 5-amino-2-fluorobenzonitrile (332 mg, 2.37 mmol)were dissolved in dry tetrahydrofuran (30 mL) under nitrogen. Thereaction mixture was cooled to 0° C. and lithiumbis(trimethylsilyl)amide in tetrahydrofuran (5.46 mL, 5.46 mmol, 1M) wasadded over a period of 2 minutes. The resulting mixture was stirred for2 minutes while cooling was continued. The mixture was quenched withsaturated aqueous ammonium chloride (15 mL) and the resulting mixturewas extracted using ethyl acetate (3×30 mL). The combined extracts werewashed with Brine (10 mL), dried on Na₂SO₄, filtered and concentrated invacuo to afford a red powder. The obtained residue was triturated in arefluxing mixture of CH₂C₂/EtOAc/methanol (10/5/5 mL). The solids werefiltered to afford a dark pink powder which was recrystallized frommethanol/water (7/0.5 mL) to afford compound 199 as a powder (325 mg)Method B: Rt: 0.99 min m/z: 451.0 (M−H)⁻ Exact mass: 452.03. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.78 (s, 3H), 3.91-4.05 (m,1H), 7.56 (t, J=9.1 Hz, 1H), 7.69 (s, 1H), 7.98 (ddd, J=9.2, 4.8, 2.8Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 10.68 (s,1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 190.1° C.

Alternative procedure for the synthesis of methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1 g,3.68 mmol) was dissolved in hot acetonitrile (5 mL), molecular sieves(about 100 mg) were added and the reaction mixture was stirred. In aseparate vessel (R)-1,1,1-trifluoro-2-propylamine (623 mg, 5.51 mmol)was dissolved in acetonitrile (5 mL), molecular sieves (about 100 mg)was added. This suspension was added to the reaction mixture and thenNaHCO₃ (926 mg, 11.0 mmol) was added. The vessel was closed and it wasstirred overnight at 80° C. The volatiles were removed under reducedpressure and the obtained residue was purified by silica gelchromatography, using a gradient from heptane to EtOAc, yielding methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1.04 g) as a white powder.

Compound 200:N-(3-Cyano-4-fluorophenyl)-4-{[2,2-difluoro-1-methylethyl]sulfamoyl}-1-methyl-1H-pyrrole-2-carboxamide

5-amino-2-fluoro-benzonitrile (5.62 g, 41.3 mmol) was added to asolution of 4-chlorosulfonyl-1-methyl-pyrrole-2-carbonyl chloride(described in the synthesis of compound 3) (10 g, 41.3 mmol), toluene(300 mL) at reflux. The reaction mixture was refluxed 4 hours andfiltered warm. The filtrate was concentrated to dryness to afford ayellow powder which was dried over weekend in vacuo. The yellow powderwas triturated in warm ethyl acetate (50 mL) and filtered and washedwith dichloromethane. The filtrate was concentrated to dryness and theresidue was purified using silica gel column chromatography (ethylacetate in heptane from 0 to 100%) to afford5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (5.05 g) as off white powder.5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (1.00 g, 2.93 mmol) was dissolved in a solution of1,1-difluoropropan-2-amine (417 mg, 4.39 mmol, synthesized according toPCT Int. Appl., 2012049277) in THF (17 mL) dried on molecular sieves andstirred at 60° C. for 20 hours. The reaction mixture was filtered andthe filtrate was evaporated to dryness. The residue was purified usingsilica gel column chromatography (ethyl acetate in heptane from 10 to70%) to afford crude compound 200 as white powder. Compound 200 waspurified by Prep SFC (Stationary phase: Chiralpak Diacel AD 20×250 mm),Mobile phase: CO₂, methanol with 0.2% iPrNH₂), the desired fractionswere collected, evaporated, solved in methanol and evaporated again,yielding compound 200 a (192 mg) as white powder. Method A: Rt: 1.67 minm/z: 399.1 (M−H)⁻ Exact mass: 400.08 ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.99 (d, J=7.0 Hz, 3H), 3.42-3.56 (m, 1H), 3.93 (s, 3H), 5.90 (td,J=56.1, 2.6 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.53 (t, J=9.2 Hz, 1H),7.64 (d, J=1.8 Hz, 1H), 7.83 (br. s., 1H), 8.01 (ddd, J=9.2, 4.8, 2.6Hz, 1H), 8.21 (dd, J=5.7, 2.6 Hz, 1H), 10.37 (s, 1H). And compound 200b(190 mg) as white powder. Method A: Rt: 1.67 min m/z: 399.0 (M−H)⁻ Exactmass: 400.08. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (d, J=7.0 Hz, 3H),3.42-3.57 (m, 1H), 3.93 (s, 3H), 5.90 (td, J=56.1, 2.6 Hz, 1H), 7.36 (d,J=1.8 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.77 (br.s., 1H), 8.01 (ddd, J=9.2, 4.9, 2.9 Hz, 1H), 8.21 (dd, J=5.9, 2.6 Hz,1H), 10.37 (br. s., 1H).

Compound 201:N-(3-Chloro-4,5-difluorophenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 201 (69 mg) as white powder was prepared similarly as describedfor compound 179 using 3-chloro-4,5-difluoro-aniline (0.18 g, 1.08 mmol)instead of 4-fluoro-3-(trifluoromethyl)aniline. The reaction was stirredat 50° C. for 92 hours. Method B: Rt: 0.98 min m/z: 432.1 (M−H)⁻ Exactmass: 433.07. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s, 3H), 2.32 (s,3H), 3.72 (s, 3H), 4.12 (d, J=6.4 Hz, 2H), 4.61 (d, J=5.9 Hz, 2H), 7.49(s, 1H), 7.71-7.81 (m, 2H), 7.93 (br. s., 1H), 10.40 (br. s., 1H).

Compound 243:N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

1,3-dimethyl-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-1H-pyrrole-2-carboxylicacid (500 mg, 1.73 mmol), 3-chloro-2,4-difluoroaniline (0.57 g, 3.47mmol) and HATU (0.88 g, 2.31 mmol) were dissolved in DMF (2 mL)containing DIPEA (0.69 mL, 3.98 mmol). The reaction mixture was stirredat 65° C. for 28 hours and at room temperature for 60 hours. Thereaction mixture was purified using silica gel column chromatography(ethyl acetate in heptane from 10 to 70%). The desired fractions werecombined and evaporated to afford a light brown oil which solidifiedwhile standing. The solid was recrystallized from ethanol (5 mL) toafford a white solid which was filtered and washed with ethanol (1 mL).The white solid was dried overnight in vacuo, resulting in compound 243(318 mg) as off white solid. Method D: Rt: 1.73 min m/z: 432.0 (M−H)⁻Exact mass: 433.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (s, 3H), 2.37(s, 3H), 3.73 (s, 3H), 4.11 (d, J=6.4 Hz, 2H), 4.61 (d, J=5.9 Hz, 2H),7.35 (td, J=9.0, 2.0 Hz, 1H), 7.47 (s, 1H), 7.67 (td, J=8.7, 5.8 Hz,1H), 7.91 (br. s., 1H), 10.03 (br. s., 1H).

Compound 202:N-(3-Chloro-4,5-difluorophenyl)-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 202 was prepared similarly as described for compound 144. InStep 4,1,3-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (260 mg, 0.83 mmol) was used and 3-chloro-4,5-difluoro-aniline(0.27 g, 1.65 mmol) instead of 3,4-difluoroaniline was used. Thisreaction was performed at 50° C. for 92 hours. The desired fractionswere combined and evaporated to afford a powder which was recrystallizedfrom CH₂Cl₂. The white crystals were filtered and washed with CH₂Cl₂ anddried overnight in vacuum oven at 50° C. to afford a white solid (170mg). Method B: Rt: 1.12 min m/z: 458.0 (M−H)⁻ Exact mass: 459.04. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz, 3H), 2.30 (s, 3H), 3.72 (s,3H), 3.78-3.90 (m, 1H), 7.53 (s, 1H), 7.66-7.84 (m, 2H), 8.18 (br. s.,1H), 10.39 (s, 1H).

Compound 203:N-(2,3-Difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Into a 100 mL round bottom flask equipped with a magnetic stir bar wasplaced methyl1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(0.9 g, 2.86 mmol), anhydrous THF (40 mL), and 2,3-difluoroaniline (490mg, 3.72 mmol). The vial was sealed and placed into an ice-water bathand to it was added LHMDS (8.6 mL of a 1M solution in THF/ethylbenzene)slowly via syringe (approx rate of 2 mL/min). Conversion to product seenafter 30 min at 0° C. Sat. aq. ammonium chloride was added to quench thereaction. This was diluted with ethyl acetate (100 mL) and the mixturepartitioned with ethyl acetate (3×100 mL). The organic layers werecombined, dried (magnesium sulfate), the solids were removed byfiltration and the solvents of the filtrate were removed under reducedpressure. The crude was partially purified via silica columnchromatography using a heptane to ethylacetate gradient. The solvent ofthe best fractions were removed under reduced pressure and the compoundwas recrystallized from ether/heptane to afford compound 203 as a whitesolid (395 mg). Method A: Rt: 1.75 min m/z: 410.1 (M−H)⁻ Exact mass:411.07. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, J=7.0 Hz, 3H),3.85-4.00 (m, 1H), 3.91 (s, 3H), 7.16-7.40 (m, 4H), 7.65 (d, J=1.8 Hz,1H), 8.17 (d, J=7.7 Hz, 1H), 10.15 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 157.94° C.

Compound 204:N-(3-Chloro-2,6-difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 204 was prepared similarly as described for compound 203 using3-chloro-2,6-difluoro-aniline (627.7 mg, 3.72 mmol) and the crude wasrecrystallized in diisopropyl ether/heptane to afford a white solid (423mg) Method A: Rt: 1.79 min m/z: 444.0 (M−H)⁻ Exact mass: 445.03. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.8 Hz, 3H), 3.84-4.01 (m, 1H), 3.91(s, 3H), 7.31 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.57-7.66 (m, 1H), 7.69(s, 1H), 8.21 (d, J=8.1 Hz, 1H), 10.17 (s, 1H).

Compound 205:N-(3-Bromo-4,5-difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 205 (893 mg) was prepared similarly as described for compound158 using 3-bromo-4,5-difluoroaniline (970 mg, 4.663 mmol) instead of3-aminobenzonitrile and stirring at 60° C. during 18 h. The obtainedresidue was warmed with CH₂Cl₂/heptanes and the white solid collected byfiltration. Method A: Rt: 1.79 min m/z: 489.9 (M−H)⁻ Exact mass: 488.98.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=7.0 Hz, 3H), 3.84-3.99 (m,1H), 3.92 (s, 3H), 7.36 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H),7.80-7.93 (m, 2H), 8.19 (br. s., 1H), 10.30 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 196.72°C.

Compound 206:N-(3-Bromo-2-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 206 (637 mg) was prepared similarly as described for compound158 using 3-bromo-2-fluoroaniline (886 mg, 4.663 mmol) instead of3-aminobenzonitrile and stirring at 60° C. during 18 h. The residue waswarmed with heptane, 1 drop EtOAc added precipitation occurs. A whitesolid was filtered off and dried in vacuo. Method A: Rt: 1.88 min m/z:470.0 (M−H)⁻ Exact mass: 470.99. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09(d, J=6.8 Hz, 3H), 3.85-4.00 (m, 1H), 3.90 (s, 3H), 7.18 (td, J=8.0, 1.3Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.50-7.60 (m, 2H), 7.65 (d, J=1.8 Hz,1H), 8.17 (br. s., 1H), 10.11 (br. s., 1H) Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 216.73° C.

Compound 207:N-(3-chloro-4,5-difluoro-phenyl)-4-[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide

5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (212.7 mg, 0.437 mmol) [112433-52-0],1-fluoro-2-methyl-propan-2-amine hydrochloride (69.7 mg, 0.546 mmol) andEt₃N (0.152 mL, 1.09 mmol) was dissolved in CH₃CN (35.4 mL, 678.73 mmol)stirred overnight and concentrated. The residue was dissolved in DMF (2mL) and purified by column chromatography on silica using a gradientfrom 10 till 100% EtOAc in heptane. The product fractions wereconcentrated. The residue was crystallized from methanol (10 mL) uponaddition of water. The white crystals of were filtered off and driedovernight in vacuo at 50° C., resulting in compound 207 (93 mg). MethodA: Rt: 2.02 min m/z: 422.0 (M−H)⁻ Exact mass: 423.06. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.17 (d, J=1.8 Hz, 6H), 3.91 (s, 3H), 4.23 (d, J=1.0 Hz,2H), 7.34 (d, J=2.0 Hz, 1H), 7.42 (s, 1H), 7.58 (d, J=1.8 Hz, 1H),7.76-7.86 (m, 2H), 10.29 (s, 1H).

Compound 208:N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 208 was prepared from ethyl4-[tert-butoxycarbonyl(isopropyl)sulfamoyl]-1,3-dimethyl-pyrrole-2-carboxylateand 3-chloro-2,4-difluoroaniline using LiHMDS in THF, followed byremoval of the Boc-protection by treatment with HCl in iPrOH/CH₂Cl₂,resulting in compound 208 (266 mg). Method B: Rt: 1.02 min m/z: 404.1(M−H)⁻ Exact mass: 405.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=6.6Hz, 6H), 2.34 (s, 3H), 3.14-3.25 (m, 1H), 3.73 (s, 3H), 7.20 (d, J=7.5Hz, 1H), 7.35 (td, J=9.0, 2.1 Hz, 1H), 7.44 (s, 1H), 7.66 (td, J=8.7,5.8 Hz, 1H), 9.99 (s, 1H).

Compound 209:N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 209 was prepared similarly as described for compound 146, using3-chloro-2,4-difluoroaniline instead of 3,4-difluoroaniline. Compound209 was recrystallized from EtOH, resulting in a white powder (211 mg).Method D: Rt: 1.97 min m/z: 458.0 (M−H)⁻ Exact mass: 459.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz, 3H), 2.35 (s, 3H), 3.73 (s, 3H),3.76-3.90 (m, 1H), 7.36 (td, J=9.0, 2.0 Hz, 1H), 7.52 (s, 1H), 7.66 (td,J=8.7, 5.8 Hz, 1H), 8.16 (br. d, J=7.3 Hz, 1H), 10.02 (s, 1H).

Compound 210:N-(3-Chloro-2,4-difluorophenyl)-1,3-dimethyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 210 was prepared similarly as described for compound 144 using3-chloro-2,4-difluoroaniline instead of 3,4-difluoroaniline. Theobtained solid was recrystallized from ethanol (5 mL) to afford compound210 (206 mg) as a white solid. Method D: Rt: 1.97 min m/z: 458.0 (M−H)⁻Exact mass: 459.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.8 Hz,3H), 2.35 (s, 3H), 3.73 (s, 3H), 3.76-3.89 (m, 1H), 7.36 (td, J=9.0, 2.0Hz, 1H), 7.52 (s, 1H), 7.66 (td, J=8.7, 5.7 Hz, 1H), 8.16 (d, J=8.6 Hz,1H), 10.02 (s, 1H).

Compound 211:4-(tert-Butylsulfamoyl)-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxamide

Compound 211 (516 mg, white crystals) was prepared similarly asdescribed for compound 214, using 3,4-difluoroaniline instead of5-amino-2-fluoro-benzonitrile.

Method D: Rt: 1.96 min m/z: 388.1 (M−H)⁻ Exact mass: 389.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20 (s, 9H), 3.79 (s, 3H), 7.35-7.48 (m, 4H),7.77-7.86 (m, 1H), 10.19 (s, 1H). Differential scanning calorimetry:From 30 to 300° C. at 10° C./min: peak at: 184.9° C.

Compound 212:4-(tert-Butylsulfamoyl)-N-(3-chloro-2,4-difluorophenyl)-3-fluoro-1-methyl-1H-pyrrole-2-carboxamide

Compound 212 (396 mg, white crystals) was prepared similarly asdescribed for compound 214, using 3-chloro-2,4-difluoro-aniline insteadof 5-amino-2-fluoro-benzonitrile. Method D: Rt: 2.05 min m/z: 422.1(M−H)⁻ Exact mass: 423.1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (s, 9H), 3.80 (s, 3H), 7.34 (d,J=2.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.60-7.70 (m, 1H), 9.80 (br. s., 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at: 230.3° C.

Compound 213:4-(tert-Butylsulfamoyl)-3-fluoro-1-methyl-N-(2,3,4-trifluorophenyl)-1H-pyrrole-2-carboxamide

Compound 213 (25 mg, white crystals) was prepared similarly as describedfor compound 214, using 2,3,4-trifluoroaniline instead of5-amino-2-fluoro-benzonitrile.

Method D: Rt: 1.97 min m/z: 406.1 (M−H)⁻ Exact mass: 407.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20 (s, 9H), 3.80 (s, 3H), 7.27-7.39 (m, 1H),7.41-7.51 (m, 3H), 9.85 (br. s, 1H). Differential scanning calorimetry:From 30 to 300° C. at 10° C./min: peak at: 223.3° C.

Compound 214:4-(tert-Butylsulfamoyl)-N-(3-cyano-4-fluorophenyl)-3-fluoro-1-methyl-H-pyrrole-2-carboxamide

A mixture of ethyl4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (purified bycolumn chromatography with 10 to 50% EtOAc in heptane, 1.50 g, 5.6mmol), tert-butylamine (934 mg, 12.8 mmol) and acetonitrile (75 mL) wasstirred 2 hours and then concentrated. The residue was dissolved inEtOAc (150 mL) washed with water, dried over sodium sulphate, filteredand concentrated yielding ethyl4-(tert-butylsulfamoyl)-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.65 g)as light yellow crystals. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 9H),1.28 (t, J=7.0 Hz, 3H), 3.82 (s, 3H), 4.27 (q, J=7.1 Hz, 2H), 7.45 (s,1H), 7.51 (d, J=4.8 Hz, 1H). Method D: Rt: 1.79 min m/z: 305.1 (M−H)⁻Exact mass: 306.1. A mixture of ethyl4-(tert-butylsulfamoyl)-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.65 g,5.4 mmol), lithium hydroxide (386 mg, 16.1 mmol), THF (20 mL) and water(5 mL) was stirred overnight. The reaction mixture was concentrated andthe obtained residue was dissolved in water (50 mL) and neutralised withHCl (1M in H₂O). The formed white crystals were filtered off and driedin vacuo at 50° C. during 4 hours, resulting in4-(tert-butylsulfamoyl)-3-fluoro-1-methyl-pyrrole-2-carboxylic acid (1.1g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (s, 9H), 3.81 (s, 3H), 7.42 (s,1H), 7.46 (d, J=4.8 Hz, 1H), 13.02 (br. s, 1H) Method B: Rt: 0.43 minm/z: 277.1 (M−H)⁻ Exact mass: 278.1.

4-(tert-butylsulfamoyl)-3-fluoro-1-methyl-pyrrole-2-carboxylic acid (100mg, 0.359 mmol), HATU (170.781 mg, 0.449 mmol), Et₃N (0.15 mL, 0.728g/mL, 1.078 mmol), 5-amino-2-fluoro-benzonitrile (97.8 mg, 0.72 mmol) inDMF (1 mL) was stirred overnight at 65° C. The solution was cooled toroom temperature and, as such, subjected to silica gel (120 g) columnchromatography using a gradient from 10 to 100% EtOAc in heptane. Theproduct fractions were concentrated and the obtained residue wasdissolved in warm methanol (10 mL). Water was added untilcrystallisation began. The crystals were filtered off and driedovernight in vacuo at 50° C., resulting in compound 214 (94 mg). MethodD: Rt: 1.87 min m/z: 395.1 (M−H)⁻ Exact mass: 396.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.20 (s, 9H), 3.80 (s, 3H), 7.44-7.49 (m, 2H), 7.53 (t,J=9.1 Hz, 1H), 7.92-8.00 (m, 1H), 8.17 (dd, J=5.7, 2.6 Hz, 1H), 10.29(s, 1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at: 198.3° C.

Compound 215:N-(3-Chloro-2,4-difluorophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 215 (94 mg, white solid) was prepared from3-chloro-2,4-difluoro-aniline and3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid similarly as described for the synthesis of compound 214 from5-amino-2-fluoro-benzonitrile and4-(tert-butylsulfamoyl)-3-fluoro-1-methyl-pyrrole-2-carboxylic acid.Method D: Rt: 1.80 min m/z: 436.1 (M−H)⁻ Exact mass: 437.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.56 (s, 3H), 3.81 (s, 3H), 4.18 (d, J=6.4 Hz, 2H),4.65 (d, J=6.2 Hz, 2H), 7.35 (td, J=9.0, 2.0 Hz, 1H), 7.53 (d, J=4.4 Hz,1H), 7.64 (td, J=8.7, 5.8 Hz, 1H), 8.32 (s, 1H), 9.87 (s, 1H).

Compound 216:3-Cyano-N-(3-cyano-4-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 171 (60 mg, 0.16 mmol) and potassium cyanide (102 mg, 1. 6mmol) were dissolved in acetonitrile (2 mL, 38.3 mmol) and heated at130° C. for 8.5 hours by microwave irradiation. The reaction mixture wasfiltered, decalite was added to the filtrate and the suspension wasevaporated to dryness. The solid was purified using silica gel columnchromatography (ethyl acetate in heptane from 10 to 100%) to affordcompound 216 as a yellow powder. Method B: Rt: 0.90 min m/z: 388.1(M−H)⁻ Exact mass: 389.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.4Hz, 6H), 3.35-3.46 (m, 1H), 3.85 (s, 3H), 7.58 (t, J=9.1 Hz, 1H), 7.72(s, 1H), 7.74 (br. s., 1H), 7.94 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.18(dd, J=5.7, 2.6 Hz, 1H), 11.15 (br. s., 1H).

Compound 217:3-Chloro-N-(3,4-difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (4 g,14.7 mmol) was dispensed in acetonitrile (20 mL),(R)-1,1,1-trifluoro-2-propylamine (2493 mg, 22.1 mmol), Hunig's base(3.8 mL, 22.1 mmol) and molecular sieves (100 mg) were added and thereaction mixture was heated overnight at 80° C. The reaction mixture wascooled down, filtered and evaporated to dryness. The obtained residuewas purified by silica gel column chromatography using a heptane toEtOAc gradient yielding methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1.76 g) as a white powder. Methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(590 mg, 1.69 mmol) and 3,4-difluoroaniline (286 mg, 2.2 mmol) weredissolved in THF (10 mL) and cooled to 0° C. Lithiumbis(trimethylsilyl)amide (1M in THF), 5.08 mL, 1 M, 5.08 mmol) was addedand the reaction mixture was allowed to reach room temperature. Thevolatiles were removed under reduced pressure to keep+/−5 mL. Theresidue was partitioned between CH₂Cl₂ and water. The water layer wasneutralised using aqueous hydrochloric acid (1M) to form a whiteprecipitate. The white solids were filtered and washed with water. Theorganic layer was loaded on a silica gel cartridge and a gradient fromheptane to EtOAc was applied. The desired fractions were evaporated tokeep+/−50 mL. A white precipitate was formed. The white solid wasfiltered and washed with heptane to afford a second solid fraction. Thetwo solids were combined and recrystallized from methanol (5 mL) toafford compound 217 (255 mg) as a white powder. The filtrate wasconcentrated to dryness and recrystallized from ethyl acetate (6 mL)heptane (20 mL) to afford more compound 217 (185 mg) as a white powderwhich was dried in vacuo. Method B: Rt: 1.06 min m/z: 444.1 (M−H)⁻ Exactmass: 445.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H),3.77 (s, 3H), 3.89-4.06 (m, 1H), 7.38-7.50 (m, 2H), 7.66 (s, 1H),7.78-7.91 (m, 1H), 8.49 (br. s., 1H), 10.56 (br. s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at: 203.9°C. (EtOAc/heptane).

Compound 218:3-Chloro-N-(3-chloro-2,4-difluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 218 was prepared similarly as described for the synthesis ofcompound 217 using 3-chloro-2,4-difluoro-aniline instead of3,4-difluoroaniline. After partitioning between CH₂Cl₂ and water, thewater layer was neutralised using aqueous hydrochloric acid (1M) to forma white precipitate. The water layer was extracted with CH₂Cl₂ (2×50 mL)and EtOAc (2×150 mL). The combined organic layers were washed with brineand dried (Na₂SO₄) and concentrated to dryness. The obtained brownpowder was recrystallized from ethyl acetate (20 mL) resulting incompound 218 (576 mg) as a powder which was dried in vacuo. Method B:Rt: 1.13 min m/z: 478.0 (M−H)⁻ Exact mass: 479.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.19 (d, J=7.0 Hz, 3H), 3.79 (s, 3H), 3.90-4.05 (m, 1H),7.37 (td, J=9.0, 2.0 Hz, 1H), 7.69 (s, 1H), 7.66-7.76 (m, 1H), 8.50 (br.s., 1H), 10.24 (s, 1H). Differential scanning calorimetry: From 30 to300° C. at 10° C./min: peak at 213.0° C.

Compound 219:3-Chloro-N-(3-chloro-2,4-difluorophenyl)-1-methyl-4-{[1-(trifluoro-methyl)cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 219 (136 mg) was prepared similarly as described for thesynthesis of compound 221 using 3-chloro-2,4-difluoro-aniline instead of5-amino-2-fluorobenzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.87(m, 2H), 2.24-2.35 (m, 2H), 2.41-2.47 (m, 2H), 3.80 (s, 3H), 7.37 (td,J=9.0, 2.1 Hz, 1H), 7.68 (s, 1H), 7.69-7.75 (m, 1H), 8.60 (br. s., 1H),10.22 (s, 1H). Method D: Rt: 2.14 min m/z: 504.0 (M−H)⁻ Exact mass:505.0. Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 237.3° C.

Compound 220:4-(tert-Butylsulfamoyl)-3-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 220 (614 mg) was prepared similarly as described for thesynthesis of compound 226 using 3-chloro-4-fluoro-aniline instead of5-amino-2-fluorobenzonitrile. Method D: Rt: 2.07 min m/z: 420.1 (M−H)⁻Exact mass: 421.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H), 3.76(s, 3H), 7.34 (s, 1H), 7.42 (t, J=9.1 Hz, 1H), 7.59 (s, 1H), 7.60-7.67(m, 1H), 7.98 (dd, J=6.7, 2.5 Hz, 1H), 10.48 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 195.9°C.

Compound 221:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-{[1-(trifluoro-methyl)cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2000mg, 7.35 mmol) was dispensed in acetonitrile (15 mL) in a microwavetube, 1-(trifluoromethyl)cyclobutan-1-amine (1.53 mg, 11.0 mmol) andHunig's base (1.9 mL, 11.03 mmol) were added and the tube was sealed andheated at 85° C. for 8 hours. The solids were filtered off and thefiltrate was evaporated to dryness. The residue was purified on silicagel using a heptane to EtOAc gradient yielding methyl3-chloro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylateas an off-white powder (382 mg). Methyl3-chloro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylate(150 mg, 0.4 mmol) and 5-amino-2-fluorobenzonitrile (0.52 mmol) weredissolved in dry THF and cooled to 0° C. Lithiumbis(trimethylsilyl)amide (1.24 mL, 1 M in THF, 1.24 mmol) was addeddropwise and the reaction mixture was allowed to reach room temperature.After 1 hour lithium bis(trimethyl-silyl)amide (0.5 mL, 1 M in THF, 0.5mmol) was added and the reaction mixture was stirred for another hour.The volatiles were removed under reduced pressure and the residue waspurified on silica gel using a heptane to EtOAc gradient. The collectedfractions were evaporated to dryness and the residue was crystallizedfrom a heptane/EtOAc mixture yielding compound 221 (91 mg) as off-whitepowder. Method D: Rt: 1.95 min m/z: 477.1 (M−H)⁻ Exact mass: 478.0. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.88 (m, 2H), 2.25-2.37 (m, 2H),2.41-2.48 (m, 2H), 3.79 (s, 3H), 7.56 (t, J=9.1 Hz, 1H), 7.68 (s, 1H),7.99 (ddd, J=9.2, 4.8, 2.6 Hz, 1H), 8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.61(s, 1H), 10.67 (s, 1H).

Compound 222:3-Chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 222 was prepared similarly as described for the synthesis ofcompound 217 using 3-chloro-4-fluoro-aniline instead of3,4-difluoroaniline. After partitioning between CH₂Cl₂ and water, thewater layer was neutralised using aqueous hydrochloric acid (1M) to forma white precipitate. The water layer was extracted with CH₂Cl₂ (4×50mL). The combined organic layers were washed with brine and dried(Na₂SO₄) and concentrated to keep (15 mL). The white solid was filteredand washed with heptane to afford compound 222 (632 mg) as off whitepowder. Method B: Rt: 1.12 min m/z: 460.1 (M−H)⁻ Exact mass: 461.0. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.77 (s, 3H),3.92-4.04 (m, 1H), 7.43 (t, J=9.0 Hz, 1H), 7.63 (ddd, J=9.0, 4.2, 2.6Hz, 1H), 7.67 (s, 1H), 7.99 (dd, J=6.8, 2.6 Hz, 1H), 8.14 (br. s., 1H),10.56 (br. s., 1H). Differential scanning calorimetry: From 30 to 300°C. at 10° C./min: peak at 218.8° C.

Compound 223:4-(tert-Butylsulfamoyl)-3-chloro-N-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 223 (579 mg) was prepared similarly as described for thesynthesis of compound 226 using 3,4-difluoroaniline instead of5-amino-2-fluorobenzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s,9H), 3.76 (s, 3H), 7.34 (s, 1H), 7.39-7.50 (m, 2H), 7.59 (s, 1H),7.78-7.91 (m, 1H), 10.50 (Br. s., 1H). Method D: Rt: 1.99 min m/z: 404.1(M−H)⁻ Exact mass: 405.1.

Compound 224:4-(tert-Butylsulfamoyl)-3-chloro-N-(3-chloro-2,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Compound 224 (405 mg) was prepared similarly as described for thesynthesis of compound 226 using 3-chloro-2,4-difluoroaniline instead of5-amino-2-fluorobenzonitrile. Method B: Rt: 1.16 min m/z: 438.1 (M−H)⁻Exact mass: 439.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H), 3.78(s, 3H), 7.31-7.40 (m, 2H), 7.61 (s, 1H), 7.65-7.75 (m, 1H), 10.16 (br.s., 1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 241.6° C.

Compound 225:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-{[(1S)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 225 was prepared similarly as described for compound 199, using(S)-1,1,1-trifluoro-2-propylamine instead of(R)-1,1,1-trifluoro-2-propylamine. Method D: Rt: 1.86 min m/z: 451.0(M−H)⁻ Exact mass: 452.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=7.0Hz, 3H), 3.78 (s, 3H), 3.92-4.05 (m, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.68(s, 1H), 7.98 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz,1H), 8.51 (br. s., 1H), 10.67 (s, 1H).

Compound 226:4-(tert-Butylsulfamoyl)-3-chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (4 g,14.7 mmol) was dispensed in acetonitrile (25 mL) and tert-butylamine(4388 mg, 58.8 mmol) was added. The reaction mixture was stirred for 30minutes at room temperature. The solids were filtered off and thefiltrate was evaporated to dryness. The residue was purified on silicausing a heptane to EtOAc gradient yielding methyl4-(tert-butylsulfamoyl)-3-chloro-1-methyl-pyrrole-2-carboxylate (3.57 g)as a white powder after trituration in CH₂Cl₂ and diisopropylether. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.14 (s, 9H), 3.82 (s, 3H), 3.86 (s, 3H),7.35 (s, 1H), 7.69 (s, 1H). Methyl4-(tert-butylsulfamoyl)-3-chloro-1-methyl-pyrrole-2-carboxylate (500 mg,1.619 mmol) and 5-amino-2-fluorobenzonitrile (295.4 mg, 2.11 mmol) weredissolved in THF (10 mL) and cooled to 0° C. Lithiumbis(trimethylsilyl)amide (5 mL, 1 M in toluene, 5 mmol) was added andthe reaction mixture was allowed to reach room temperature. More lithiumbis(trimethylsilyl)amide (1 mL, 1M in THF, 1 mmol) was added and thereaction mixture was stirred for 30 minutes more. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ and water. The organic layer was loaded on a silica cartridge anda gradient form heptane to EtOAc was applied. The desired fractions wereevaporated to dryness and the residue was crystallized from aEtOAc/heptane mixture. The precipitate was filtered off, triturated withdiisopropylether and dried, yielding compound 226 (513 mg) as a whitepowder. Method B: Rt: 1.01 min m/z: 411.2 (M−H)⁻ Exact mass: 412.1. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 9H), 3.77 (s, 3H), 7.36 (s, 1H),7.55 (t, J=9.1 Hz, 1H), 7.61 (s, 1H), 7.99 (ddd, J=9.2, 4.8, 2.8 Hz,1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 10.61 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 207.0° C.

Compound 227:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[1-(trifluoromethyl)cyclopropyl]sulfamoyl}-1H-pyrrole-2-carboxamide

5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (600 mg, 1.76 mmol) was mixed with1-trifluoromethyl-1-cyclopropylamine (329 mg, 2.63 mmol), acetonitrile(10 mL), molecular sieves and Hunig's base (0.91 mL, 0.75 g/mL, 5.27mmol) in a microwave vial (20 mL) and stirred at 100° C. for 1 hour andnext at 110° C. for 1 hour under MW-irradiation. The reaction mixturewas filtered and the filtrate concentrated to dryness. The obtainedresidue was purified using silica gel column chromatography (ethylacetate in heptane from 10 to 70%) and further by preparative HPLC(Stationary phase: Uptisphere C18 ODB—10 μm, 200 g, 5 cm, Mobile phase:0.25% NH₄HCO₃ solution in water, CH₃CN), resulting in compound 227 (63mg) after concentration and drying in vacuo at 50° C.

Method B: Rt: 0.98 min m/z: 429.1 (M−H)⁻ Exact mass: 430.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.09-1.21 (m, 4H), 3.91 (s, 3H), 7.31 (d, J=2.0 Hz,1H), 7.53 (t, J=9.1 Hz, 1H), 7.56-7.58 (m, 1H), 8.01 (ddd, J=9.2, 5.0,2.8 Hz, 1H), 8.21 (dd, J=5.8, 2.8 Hz, 1H), 8.74 (br. s., 1H), 10.36 (br.s., 1H).

Compound 228:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[3-(trifluoromethyl)tetrahydrofuran-3-yl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 228 (153 mg) was prepared similarly as described for compound227, using 3-(trifluoromethyl)tetrahydrofuran-3-amine hydrochlorideinstead of 1-trifluoromethyl-1-cyclopropylamine. Racemic compound 228was separated in enantiomers by Prep SFC (Stationary phase: ChiralpakDaicel IC 20×250 mm, Mobile phase: CO₂, 12-50% MeOH with 0.4% iPrNH₂),resulting in compound 228a (first eluding) and 228b (second eluding, 41mg). 228a was further purified by Prep HPLC (Stationary phase: RPXBridge Prep C18 OBD-10m, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃solution in water, CH₃CN) resulting in compound 228a (28 mg) as whitesolid. 228a: Method D: Rt: 1.79 min m/z: 459.0 (M−H)⁻ Exact mass: 460.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.18 (dt, J=13.8, 8.1 Hz, 1H), 2.42-2.49(m, 1H), 3.60 (q, J=7.8 Hz, 1H), 3.83 (td, J=8.3, 4.4 Hz, 1H), 3.92 (s,3H), 3.91-3.96 (m, 1H), 4.04-4.10 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.53(t, J=9.1 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 8.01 (ddd, J=9.2, 4.8, 2.9Hz, 1H), 8.21 (dd, J=5.8, 2.8 Hz, 1H), 8.49 (br. s., 1H), 10.39 (s, 1H).228b: Method D: Rt: 1.79 min m/z: 459.0 (M−H)⁻ Exact mass: 460.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.20 (dt, J=13.8, 8.1 Hz, 1H), 2.43-2.49 (m,1H), 3.60 (q, J=7.7 Hz, 1H), 3.79-3.88 (m, 1H), 3.92 (s, 3H), 3.91-3.96(m, 1H), 4.04-4.10 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.53 (t, J=9.1 Hz,1H), 7.62 (d, J=1.8 Hz, 1H), 8.01 (ddd, J=9.3, 4.9, 2.8 Hz, 1H), 8.21(dd, J=5.7, 2.6 Hz, 1H), 8.46 (br. s., 1H), 10.38 (s, 1H).

Synthesis of 3-(trifluoromethyl)tetrahydrofuran-3-amine hydrochloride

A mixture of 3-oxotetrahydrofuran (30 g, 348.5 mmol), benzylamine (39.2g, 365.8 mmol), MgSO₄ (21 g, 174.5 mmol) and CH₂Cl₂ (200 mL) was stirredat 28° C. for 24 hours. The mixture was filtrated. The filtrate wasconcentrated in vacuo and the obtained residue (63.1 g) was useddirectly in the next step. The obtained residue (63 g) was dissolved inacetonitrile (600 mL).

Trifluoroacetic acid (45 g, 394 mmol), potassium hydrogenfluoride (22.5g, 288 mmol) and DMF (60 mL) were added to the mixture at 0° C. Themixture was stirred at 00 for 10 minutes.(trifluoromethyl)trimethylsilane (77 g, 541 mmol) was added to thereaction mixture and the mixture was stirred at ambient temperature for12 h. Saturated aqueous Na₂CO₃ (200 mL) was added and the mixture wasstirred for 5 min. The mixture was diluted with water (500 mL), andextracted with ethyl acetate (3×300 mL). The combined organic layerswere washed with water and brine, dried over Na₂SO₄ and evaporated underreduced pressure. The obtained residue was dissolved in 2M HCl/MeOH andthe solvent was evaporated.

The resulting hydrochloride salt was crystallized from CH₃CN to provideN-benzyl-3-(trifluoromethyl)tetrahydrofuran-3-amine (30.5 g). A mixtureof N-benzyl-3-(trifluoromethyl)tetrahydrofuran-3-amine (30.5 g),palladium on alumina (1.5 g) and MeOH was stirred under H₂ (20 psi)atmosphere at 28° C. for 12 hours.

The mixture was filtered and the filtrate was concentrated in vacuoresulting in 3-(trifluoromethyl)tetrahydrofuran-3-amine hydrochloride(20.5 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21-2.43 (m, 2H) 3.83-4.16(m, 4H) 9.68 (br. s., 3H).

Compound 229:N-(3,4-Difluorophenyl)-3-fluoro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

To ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=7.0 Hz, 3H), 1.28 (t, J=7.0Hz, 3H), 3.83 (s, 3H), 3.90-4.02 (m, 1H), 4.28 (q, J=7.0 Hz, 2H), 7.60(d, J=4.6 Hz, 1H), 8.59 (d, J=8.8 Hz, 1H); 1.10 g, 3.18 mmol) and3,4-difluoroaniline (534 mg, 4.14 mmol) dissolved in THF (47 mL) undernitrogen atmosphere, at 0° C., lithium bis(trimethylsilyl)amide (12.7mL, 1 M in toluene, 12.72 mmol) was added. The mixture was stirred 1hour at 0° C. and further overnight at room temperature. The reactionmixture was quenched with NH₄Cl (30 mL) solution and extracted withEtOAc (50 mL), diluted with brine (50 mL) and extracted again with EtOAc(50 mL). The combined organic layers were dried over sodium sulphate,filtered and concentrated. The residue (dissolved in 1 mL DMF) waspurified by column chromatography on silica (120 g) with a gradient from10 till 100% EtOAc in heptane. The product fractions were concentratedand the solid residue was crystallized from warm methanol (20 mL) uponaddition of water. The white crystals were filtered off and dried invacuo at 50° C. overnight, resulting in compound 229 (945 mg). Method D:Rt: 1.93 min m/z: 428.1 (M−H)⁻ Exact mass: 429.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.18 (d, J=7.0 Hz, 3H), 3.80 (s, 3H), 3.91-4.04 (m, 1H),7.37-7.48 (m, 2H), 7.54 (d, J=4.4 Hz, 1H), 7.76-7.86 (m, 1H), 8.59 (d,J=8.6 Hz, 1H), 10.26 (s, 1H).

Compound 230:N-(3-Bromo-4-fluorophenyl)-3-fluoro-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

3-fluoro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylic acid (153mg, 0.579 mmol), HATU (275 mg, 0.724 mmol), Et₃N (0.242 mL, 1.74 mmol),3-bromo-4-fluoro-aniline (220 mg, 1.16 mmol) and DMF (1.1 mL) werestirred overnight at 65° C. The solution was subjected to columnchromatography on a 120 g Reveleris silica gel cartridge using agradient from 10 till 100% EtOAc in heptane. The product fractions wereconcentrated. The residue was dissolved in warm methanol (50 mL). Waterwas added until crystallisation began. The white crystals were filteredoff and dried overnight in vacuo at 50° C. Method D: Rt: 2.04 min m/z:436.2 (M−H)⁻ Exact mass: 437.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d,J=6.6 Hz, 6H), 3.31-3.40 (m, 1H), 3.79 (s, 3H), 7.37 (t, J=8.8 Hz, 1H),7.45 (d, J=4.4 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.64 (ddd, J=9.0, 4.4,2.6 Hz, 1H), 8.08 (dd, J=6.4, 2.4 Hz, 1H), 10.18 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 200.9°C.

Compound 231:N-(3-Cyano-2,4-difluorophenyl)-3-fluoro-1-methyl-4-[(1-methyl-ethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 231 (88 mg) was prepared similarly as described for compound230, using 3-amino-2,6-difluoro-benzonitrile instead of3-bromo-4-fluoro-aniline. Method D: Rt: 1.86 min m/z: 399.3 (M−H)⁻ Exactmass: 400.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.4 Hz, 6H),3.31-3.40 (m, 1H), 3.81 (s, 3H), 7.41-7.52 (m, 2H), 7.61 (d, J=7.3 Hz,1H), 8.03 (td, J=8.9, 6.2 Hz, 1H), 9.96 (s, 1H).

Compound 232:N-(3,4-Difluorophenyl)-3-fluoro-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 232 (144 mg) was prepared similarly as described for compound230, using 3,4-difluoroaniline instead of 3-bromo-4-fluoro-aniline.Method D: Rt: 1.95 min m/z: 374.3 (M−H)⁻ Exact mass: 375.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.05 (d, J=6.6 Hz, 6H), 3.31-3.41 (m, 1H), 3.79 (s,3H), 7.35-7.49 (m, 3H), 7.57 (d, J=7.3 Hz, 1H), 7.76-7.87 (m, 1H), 10.22(s, 1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 195.8° C.

Compound 233:3-Fluoro-1-methyl-4-[(1-methylethyl)sulfamoyl]-N-(2,3,4-trifluorophenyl)-1H-pyrrole-2-carboxamide

Compound 233 (89 mg) was prepared similarly as described for compound230, using 2,3,4-trifluoroaniline instead of 3-bromo-4-fluoro-aniline.Method D: Rt: 1.95 min m/z: 392.3 (M−H)⁻ Exact mass: 393.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.6 Hz, 6H), 3.31-3.40 (m, 1H), 3.80 (s,3H), 7.28-7.39 (m, 1H), 7.41-7.51 (m, 2H), 7.59 (d, J=7.3 Hz, 1H), 9.87(s, 1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 214.3° C.

Compound 234:N-(3-Chloro-2,4-difluorophenyl)-3-fluoro-1-methyl-4-[(1-methyl-ethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 234 (95 mg) was prepared similarly as described for compound230, using 3-chloro-2,4-difluoro-aniline instead of3-bromo-4-fluoro-aniline. Method D: Rt: 2.03 min m/z: 408.3 (M−H)⁻ Exactmass: 409.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.4 Hz, 6H),3.31-3.40 (m, 1H), 3.81 (s, 3H), 7.35 (td, J=9.0, 2.1 Hz, 1H), 7.48 (d,J=4.6 Hz, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.65 (td, J=8.7, 5.8 Hz, 1H),9.83 (s, 1H).

Compound 235:N-(3-Chloro-4-fluorophenyl)-3-fluoro-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 235 (156 mg) was prepared similarly as described for compound230, using 3-chloro-4-fluoro-aniline instead of3-bromo-4-fluoro-aniline. Method D: Rt: 2.03 min m/z: 390.3 (M−H)⁻ Exactmass: 391.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J=6.6 Hz, 6H),3.31-3.40 (m, 1H), 3.80 (s, 3H), 7.40 (t, J=9.1 Hz, 1H), 7.45 (d, J=4.6Hz, 1H), 7.54-7.64 (m, 2H), 7.96 (dd, J=6.8, 2.4 Hz, 1H), 10.19 (s, 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 201.9° C.

Compound 236:N-(3-Chloro-2,4-difluorophenyl)-4-{[2,2-difluorocyclopentyl]sulfamoyl}-1-methyl-1H-pyrrole-2-carboxamide

5-[(3-chloro-2,4-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (532.5 mg, 1.442 mmol), 2,2-difluorocyclopentan-1-aminehydrochloride (261 mg, 1.66 mmol) and Et₃N (0.501 mL, 3.61 mmol) inacetonitrile (50 mL) was stirred and refluxed 2 hours. The reactionmixture was concentrated and the obtained residue was dissolved in EtOAc(50 mL) washed with HCl 1M, dried over sodium sulphate, filtered andconcentrated. The obtained residue was subjected to silica gel columnchromatography using a gradient from 10 till 100% EtOAc in heptane. Theproduct fractions were concentrated resulting in compound 236 (518 mg)as a white solid.

Racemic compound 236 was separated in its enantiomers 236a (firsteluding) and 236b (second eluding) via Prep SFC (Stationary phase:Chiralpak Diacel AD 20×250 mm, Mobile phase: CO₂, 30% EtOH-iPrOH (50-50)with 0.2% iPrNH₂)

236a: Method D: Rt: 1.98 min m/z: 452.3 (M−H)⁻ Exact mass: 453.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.41-1.72 (m, 3H), 1.76-1.87 (m, 1H), 1.90-2.18(m, 2H), 3.61-3.78 (m, 1H), 3.89 (s, 3H), 7.31-7.38 (m, 2H), 7.53 (td,J=8.7, 5.9 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H),10.12 (s, 1H).

236b: Method D: Rt: 1.98 min m/z: 452.3 (M−H)⁻ Exact mass: 453.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.40-1.74 (m, 3H), 1.75-1.89 (m, 1H), 1.90-2.18(m, 2H), 3.62-3.78 (m, 1H), 3.89 (s, 3H), 7.29-7.39 (m, 2H), 7.48-7.61(m, 2H), 7.81 (d, J=8.1 Hz, 1H), 10.12 (s, 1H).

Compound 237:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-di-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.25 g, 0.73 mmol) was dissolved in acetonitrile (6 mL) anddried with molecular sieves 4A powder over a period of 30 minutes in apressure tube. 2,2,2-trifluoro-1,1-dimethyl-ethylamine (139 mg, 1.1mmol) and sodium bicarbonate (307.3 mg, 3.66 mmol) were dispersed inacetonitrile (2 mL), dried with molecular sieves 4A powder over a periodof 30 minutes and the resulting mixture was added to the pressure tube,which was flushed with nitrogen, capped and stirred in a heating blockat 80° C. for 24 hours. Then the reaction mixture was filtered andrinsed using dichloromethane (50 mL). The filtrate was concentrated invacuo and the obtained residue was purified using silica gel columnchromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). Thedesired fractions were concentrated under reduced pressure and theobtained powder was dried in a vacuum oven at 55° C. for 24 hoursyielding compound 237 (213 mg). Method D: Rt: 1.89 min m/z: 431.1 (M−H)⁻Exact mass: 432.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 6H), 3.93(s, 3H), 7.35 (d, J=2.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.59 (d, J=1.8Hz, 1H), 7.84-8.15 (m, 2H), 8.21 (dd, J=5.9, 2.6 Hz, 1H), 10.38 (br. s.,1H).

Compound 238:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-[(3,3,3-trifluoro-1-methyl-propyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 238 (206 mg) was prepared similarly as described for compound237, using 4,4,4-trifluorobutan-2-amine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction timeinstead of 24 hours. Method D: Rt: 1.86 min m/z: 431.1 (M−H)⁻ Exactmass: 432.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (d, J=6.6 Hz, 3H),2.29-2.47 (m, 2H), 3.50 (sxt, J=6.6 Hz, 1H), 3.93 (s, 3H), 7.36 (d,J=2.0 Hz, 1H), 7.40-7.88 (m, 3H), 8.01 (ddd, J=9.2, 5.0, 2.8 Hz, 1H),8.22 (dd, J=5.8, 2.8 Hz, 1H), 10.38 (br. s., 1H).

Compound 239:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[(1S)-1-(trifluoromethyl)-propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 239 (236 mg) was prepared similarly as described for compound237, using (S)-1-trifluoromethyl-propylamine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method D: Rt: 1.89 min m/z:431.1 (M−H)⁻ Exact mass: 432.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t,J=7.4 Hz, 3H), 1.32-1.51 (m, 1H), 1.56-1.74 (m, 1H), 3.68-3.85 (m, 1H),3.95 (s, 3H), 7.37 (d, J=2.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.64 (d,J=1.8 Hz, 1H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1H), 8.06-8.33 (m, 2H),10.37 (br. s., 1H).

Compound 240:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[(1R)-1-(trifluoromethyl)-propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 240 (244 mg) was prepared similarly as described for compound237, using (R)-1-trifluoromethyl-propylamine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine Method D: Rt: 1.89 min m/z:431.1 (M−H)⁻ Exact mass: 432.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t,J=7.4 Hz, 3H), 1.35-1.53 (m, 1H), 1.55-1.73 (m, 1H), 3.62-3.83 (m, 1H),3.92 (s, 3H), 7.37 (d, J=1.8 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.63 (d,J=1.5 Hz, 1H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.06-8.51 (m, 2H),10.37 (br. s., 1H).

Compound 241:N-(3-Cyano-4-fluorophenyl)-1-methyl-4-{[1-(trifluoromethyl)cyclo-butyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 241 (119 mg) was prepared similarly as described for compound237, using 1-trifluoromethyl-cyclobutylamine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction timeinstead of 24 hours. Method D: Rt: 1.91 min m/z: 443.1 (M−H)⁻ Exactmass: 444.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.90 (m, 2H),2.23-2.36 (m, 2H), 2.39-2.48 (m, 2H), 3.94 (s, 3H), 7.39 (d, J=1.8 Hz,1H), 7.53 (t, J=9.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 8.02 (ddd, J=9.2,5.0, 2.8 Hz, 1H), 8.22 (dd, J=5.8, 2.8 Hz, 1H), 8.37 (br. s., 1H), 10.39(br. s., 1H).

Compound 242:N-(3-Cyano-4-fluorophenyl)-4-{[2-fluoro-1-(fluoromethyl)ethyl]sulfamoyl}-1-methyl-1H-pyrrole-2-carboxamide

Compound 242 (162 mg) was prepared similarly as described for compound237, using 1,3-difluoropropan-2-amine hydrochloride instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method D: Rt: 1.70 min m/z:399.0 (M−H)⁻ Exact mass: 400.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.50-3.76 (m, 1H), 3.92 (s, 3H), 4.26-4.54 (m, 4H), 7.37 (d, J=2.0 Hz,1H), 7.53 (t, J=9.1 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.73-8.17 (m, 2H),8.22 (dd, J=5.8, 2.8 Hz, 1H), 10.38 (br. s., 1H).

Compound 244:N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[(1-methylcyclopropyl)-sulfamoyl]pyrrole-2-carboxamide

Compound 244 (144 mg) was prepared similarly as described for compound237, using (1-methylcyclopropyl)amine hydrochloride instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method B: Rt: 0.93 min m/z:375.1 (M−H)⁻ Exact mass: 376.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.30-0.47 (m, 2H), 0.63-0.73 (m, 2H), 1.18 (s, 3H), 3.93 (s, 3H), 7.33(d, J=2.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.68(s, 1H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1H), 8.22 (dd, J=5.9, 2.6 Hz,1H), 10.36 (s, 1H).

Compound 245:N-(3-cyano-4-fluoro-phenyl)-4-[(3,3-difluoro-1-methyl-cyclobutyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 245 (243 mg) was prepared similarly as described for compound237, using 3,3-difluoro-1-methylcyclobutanamine hydrochloride instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method B: Rt: 0.99 min m/z:425.2 (M−H)⁻ Exact mass: 426.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (s,3H), 2.40-2.57 (m, 2H), 2.74-2.95 (m, 2H), 3.93 (s, 3H), 7.35 (d, J=2.0Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.87 (br. s.,1H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.21 (dd, J=5.7, 2.6 Hz, 1H),10.37 (br. s., 1H).

Compound 246:N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[1-methyl-1-(trifluoro-methyl)propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 246 (130 mg) was prepared similarly as described for compound237, using 1,1,1-trifluoro-2-methylbutan-2-amine hydrochloride insteadof 2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction timeinstead of 24 hours.

Method B: Rt: 1.05 min m/z: 445.2 (M−H)⁻ Exact mass: 446.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.79 (t, J=7.4 Hz, 3H), 1.37 (s, 3H), 1.46-1.58 (m,1H), 1.73-1.89 (m, 1H), 3.92 (s, 3H), 7.35 (d, J=1.8 Hz, 1H), 7.53 (t,J=9.1 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.89 (br. s., 1H), 8.02 (ddd,J=9.2, 4.9, 2.9 Hz, 1H), 8.21 (dd, J=5.8, 2.8 Hz, 1H), 10.37 (s, 1H).

Compound 247:N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-{[4-(trifluoromethyl)tetrahydropyran-4-yl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 247 (23 mg) was prepared similarly as described for compound237, using 4-(trifluoromethyl)oxan-4-amine hydrochloride instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine and 48 hours reaction timeinstead of 24 hours. An extra purification was performed via Prep HPLC(Stationary phase: RP XBridge Prep C18 OBD-10 m, 30×150 mm, Mobilephase: 0.25% NH₄HCO₃ solution in water, MeOH). Method B: Rt: 0.96 minm/z: 473.1 (M−H)⁻ Exact mass: 474.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.64-1.79 (m, 2H), 2.11 (d, J=13.4 Hz, 2H), 3.50 (t, J=11.4 Hz, 2H),3.70-3.81 (m, 2H), 3.93 (s, 3H), 7.36 (d, J=1.8 Hz, 1H), 7.53 (t, J=9.1Hz, 1H), 7.57-7.65 (m, 1H), 7.92 (br. s., 1H), 8.02 (ddd, J=9.2, 4.8,2.9 Hz, 1H), 8.22 (dd, J=5.8, 2.8 Hz, 1H), 10.41 (br. s., 1H).

Compound 248:N-(3-cyano-4-fluoro-phenyl)-4-{[1-ethyl-1-(trifluoromethyl)propyl]sulfamoyl}-1-methyl-1H-pyrrole-2-carboxamide

Compound 248 (40 mg) was prepared similarly as described for compound237, using 3-(trifluoromethyl)pentan-3-amine hydrochloride instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method B: Rt: 1.11 min m/z:459.2 (M−H)⁻ Exact mass: 460.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82 (t,J=7.4 Hz, 6H), 1.70-1.83 (m, 2H), 1.84-1.97 (m, 2H), 3.92 (s, 3H), 7.34(d, J=1.8 Hz, 1H), 7.47-7.61 (m, 2H), 7.73 (br. s., 1H), 8.02 (ddd,J=9.2, 4.8, 2.9 Hz, 1H), 8.21 (dd, J=5.7, 2.6 Hz, 1H), 10.38 (br. s.,1H).

Compound 249:N-(3-cyano-4-fluoro-phenyl)-4-[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 249 (178 mg) was prepared similarly as described for compound237, using 1-fluoro-2-methylpropan-2-amine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine Method B: Rt: 0.94 min m/z:395.1 (M−H)⁻ Exact mass: 396.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.13-1.20 (m, 6H), 3.92 (s, 3H), 4.24 (d, J=47.5 Hz, 2H), 7.35 (d, J=2.0Hz, 1H), 7.41 (br. s., 1H), 7.53 (t, J=9.1 Hz, 1H), 7.58 (d, J=1.8 Hz,1H), 8.01 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.22 (dd, J=5.9, 2.6 Hz, 1H),10.36 (br. s., 1H).

Compound 250:N-(3-Bromophenyl)-3-chloro-1-methyl-4-{[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl}-1H-pyrrole-2-carboxamide

3-bromoaniline (92 mg, 0.53 mmol) and methyl3-chloro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(143 mg, 0.41 mmol) were dissolved in THF (10 mL). Lithiumbis(trimethylsilyl)amide (1M in THF) (1.23 mL, 1 M, 1.23 mmol) was addedand the reaction mixture was stirred overnight. The reaction mixture wasquenched with sat. NH₄Cl (aq) (5 mL). The aqueous layer was extractedwith CH₂Cl₂ (2×5 mL). The combined organic layers were evaporated todryness and the residue was purified on silica using a heptane to EtOAcgradient. The obtained products was crystallized from CH₂Cl₂, trituratedwith diisopropylether and dried yielding, compound 250 (156 mg) as awhite powder. Method D: Rt: 2.05 min m/z: 487.9 (M−H)⁻ Exact mass:489.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=7.0 Hz, 3H), 3.77 (s,3H), 3.91-4.01 (m, 1H), 7.29-7.37 (m, 2H), 7.61-7.69 (m, 2H), 7.97-8.04(m, 1H), 8.48 (s, 1H), 10.51 (s, 1H). Differential scanning calorimetry:From 30 to 300° C. at 10° C./min: peak at 197.9° C.

Compound 251:N-(3-Bromophenyl)-3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide

3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylicacid (250 mg, 0.855 mmol), HATU (407 mg, 1.07 mmol), Et₃N (0.36 mL, 2.57mmol) and 3-bromoaniline (294 mg, 1.71 mmol) in DMF (4 mL) were stirred4 hours at 65° C. The solution was subjected to column chromatography ona 120 g silica gel Reveleris cartridge using a gradient from 10 till100% EtOAc in heptane. The product fractions were concentrated andcompound 251 was crystallized by dissolving the obtained liquid residuein methanol (30 mL) upon addition of water. The white crystals werefiltered off and dried overnight in vacuo at 50° C. Method D: Rt: 1.81min m/z: 446.0 (M−H)⁻ Exact mass: 447.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.56 (s, 3H), 3.80 (s, 3H), 4.17 (d, J=6.4 Hz, 2H), 4.65 (d, J=6.2 Hz,2H), 7.26-7.35 (m, 2H), 7.50 (d, J=4.6 Hz, 1H), 7.62 (dt, J=6.5, 2.4 Hz,1H), 7.96-8.01 (m, 1H), 8.30 (s, 1H), 10.19 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 193.4°C.

Compound 252:N-(3-chloro-2,4-difluoro-phenyl)-4-[(2,2-difluoro-1-methyl-ethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

5-[(3-chloro-2,4-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (0.25 g, 0.68 mmol) was dissolved in acetonitrile (6 mL) in apressure tube and this was dried with powdered molecular sieves (4A)over a period of 30 minutes. Another tube was loaded with1,1-difluoropropan-2-amine (1.0 mmol) and sodium bicarbonate (284 mg,3.39 mmol) and this was dispersed in acetonitrile (2 mL) and dried withpowdered molecular sieves (4A) over a period of 30 minutes. This wasadded to the pressure tube which was flushed with nitrogen, capped andstirred in a heating block at 80° C. for 24 hours. Then the reactionmixture was filtered and rinsed using dichloromethane (50 mL). Thefiltrate was concentrated in vacuo and the obtained residue was purifiedusing silica gel column chromatography (gradient elution: EtOAc-heptane0:100 to 100:0). The obtained powder was dried in a vacuum oven at 55°C. for 24 hours yielding compound 252 (204 mg) as a white powder. MethodB: Rt: 1.00 min m/z: 426.1 (M−H)⁻ Exact mass: 427.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.01 (d, J=7.0 Hz, 3H), 3.39-3.59 (m, 1H), 3.92 (s, 3H),5.91 (td, J=55.9, 2.4 Hz, 1H), 7.29-7.39 (m, 2H), 7.46-7.58 (m, 1H),7.63 (d, J=1.5 Hz, 1H), 7.85 (br. s., 1H), 10.14 (br. s., 1H).

Compound 253:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[1-(trifluoromethyl)-cyclopropyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 253 (104 mg) was prepared similarly as described for compound252, using 1-trifluoromethyl-1-cyclopropylamine instead of1,1-difluoropropan-2-amine and 48 hours reaction time instead of 24hours. An extra purification was performed via Prep HPLC (Stationaryphase: RP XBridge Prep C18 OBD-10μm, 30×150 mm, Mobile phase: 0.25%NH₄HCO₃ solution in water, MeOH). Method B: Rt: 1.05 min m/z: 456.1(M−H)⁻ Exact mass: 457.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.24 (m,4H), 3.89 (s, 3H), 7.29 (d, J=1.8 Hz, 1H), 7.35 (td, J=9.0, 1.9 Hz, 1H),7.46-7.56 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 8.65 (br. s, 1H), 10.13 (br.s., 1H).

Compound 254:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethyl-ethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 254 (75 mg) was prepared similarly as described for compound252, using 2,2,2-trifluoro-1,1-dimethyl-ethylamine instead of1,1-difluoropropan-2-amine. An extra purification was performed via PrepHPLC (Stationary phase: RP XBridge Prep C18 OBD-10m, 30×150 mm, Mobilephase: 0.25% NH₄HCO₃ solution in water, MeOH). Method B: Rt: 1.09 minm/z: 458.1 (M−H)⁻ Exact mass: 459.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.37 (s, 6H), 3.90 (s, 3H), 7.28-7.42 (m, 2H), 7.47-7.57 (m, 1H), 7.59(d, J=1.8 Hz, 1H), 8.08 (br. s., 1H), 10.16 (br. s., 1H).

Compound 255:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-[(1-methylcyclopropyl)-sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 255 (211 mg) was prepared similarly as described for compound252, using (1-methylcyclopropyl)amine hydrochloride instead of1,1-difluoropropan-2-amine. Method B: Rt: 1.00 min m/z: 402.1 (M−H)⁻Exact mass: 403.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.36-0.44 (m, 2H),0.66-0.75 (m, 2H), 1.20 (s, 3H), 3.90 (s, 3H), 7.30 (d, J=2.0 Hz, 1H),7.34 (td, J=8.9, 2.0 Hz, 1H), 7.48-7.55 (m, 1H), 7.56 (d, J=1.5 Hz, 1H),7.67 (br. s., 1H), 10.13 (br. s., 1H).

Compound 256:N-(3-chloro-2,4-difluoro-phenyl)-4-[(3,3-difluoro-1-methyl-cyclo-butyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 256 (258 mg) was prepared similarly as described for compound252, using 3,3-difluoro-1-methylcyclobutanamine instead of1,1-difluoropropan-2-amine. Method B: Rt: 1.05 min m/z: 452.1 (M−H)⁻Exact mass: 453.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (s, 3H),2.43-2.57 (m, 2H), 2.73-2.94 (m, 2H), 3.90 (s, 3H), 7.30-7.40 (m, 2H),7.48-7.57 (m, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.87 (br. s., 1H), 10.14 (br.s., 1H).

Compound 257:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[1-methyl-1-(trifluoro-methyl)propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 257 (71 mg) was prepared similarly as described for compound252, using 1,1,1-trifluoro-2-methylbutan-2-amine hydrochloride insteadof 1,1-difluoropropan-2-amine and 48 h reaction time instead of 24 h. Anextra purification was performed via Prep HPLC (Stationary phase: RPXBridge Prep C18 OBD-10 m, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃solution in water, MeOH). Method B: Rt: 1.13 min m/z: 472.1 (M−H)⁻ Exactmass: 473.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (t, J=7.3 Hz, 3H),1.38 (s, 3H), 1.53 (dq, J=14.0, 7.2 Hz, 1H), 1.73-1.89 (m, 1H), 3.89 (s,3H), 7.29-7.39 (m, 2H), 7.47-7.56 (m, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.89(br. s., 1H), 10.14 (br. s., 1H).

Compound 258:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-[[4-(trifluoromethyl)-tetrahydropyran-4-yl]sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 258 (29 mg) was prepared similarly as described for compound252, using 4-(trifluoromethyl)oxan-4-amine hydrochloride instead of1,1-difluoropropan-2-amine and 48 h reaction time instead of 24 h. Anextra purification was performed via Prep HPLC (Stationary phase: RPXBridge Prep C18 OBD-10 m, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃solution in water, MeOH). Method B: Rt: 1.03 min m/z: 500.1 (M−H)⁻ Exactmass: 501.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.78 (m, 2H),2.06-2.18 (m, 2H), 3.51 (t, J=11.4 Hz, 2H), 3.71-3.82 (m, 2H), 3.90 (s,3H), 7.27-7.41 (m, 2H), 7.49-7.57 (m, 1H), 7.57-7.61 (m, 1H), 7.91 (br.s., 1H), 10.17 (br. s., 1H).

Compound 259:N-(3-chloro-2,4-difluoro-phenyl)-4-[[1-ethyl-1-(trifluoromethyl)-propyl]sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 259 (114 mg) was prepared similarly as described for compound252, using 3-(trifluoromethyl)pentan-3-amine hydrochloride instead of1,1-difluoropropan-2-amine. Method B: Rt: 1.16 min m/z: 486.1 (M−H)⁻Exact mass: 487.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (t, J=7.4 Hz,6H), 1.68-2.02 (m, 4H), 3.90 (s, 3H), 7.29-7.41 (m, 2H), 7.47-7.54 (m,1H), 7.55 (d, J=1.5 Hz, 1H), 7.62-7.94 (m, 1H), 10.14 (br. s., 1H).

Compound 260:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-[(3,3,3-trifluoro-1-methylpropyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 260 (252 mg) was prepared similarly as described for compound252, using 4,4,4-trifluorobutan-2-amine instead of1,1-difluoropropan-2-amine. Method B: Rt: 1.06 min m/z: 458.1 (M−H)⁻Exact mass: 459.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.6 Hz,3H), 2.24-2.49 (m, 2H), 3.50 (sxt, J=6.5 Hz, 1H), 3.92 (s, 3H),7.20-7.41 (m, 2H), 7.42-7.81 (m, 3H), 10.13 (br. s., 1H).

Compound 261:N-(3-chloro-2,4-difluoro-phenyl)-4-[(2-fluoro-1,1-dimethyl-ethyl)sulfamoyl]-1-methyl-1H-pyrrole-2-carboxamide

Compound 261 (143 mg) was prepared similarly as described for compound252, using 1-fluoro-2-methylpropan-2-amine instead of1,1-difluoropropan-2-amine. The desired fractions were concentratedunder reduced pressure yielding a powder. An extra purification wasperformed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10m,30×150 mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, MeOH). MethodB: Rt: 1.03 min m/z: 422.1 (M−H)⁻ Exact mass: 423.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13-1.22 (m, 6H), 3.90 (s, 3H), 4.24 (d, J=47.3 Hz, 2H),7.29-7.37 (m, 2H), 7.41 (br. s., 1H), 7.49-7.55 (m, 1H), 7.56 (d, J=1.8Hz 1H), 10.13 (br. s., 1H).

Compound 262:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[(1S)-1-(trifluoro-methyl)propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 262 (227 mg) was prepared similarly as described for compound252, using (S)-1-trifluoromethyl-propylamine instead of1,1-difluoropropan-2-amine.

Method B: Rt: 1.08 min m/z: 458.1 (M−H)⁻ Exact mass: 459.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.73 (t, J=7.5 Hz, 3H), 1.38-1.52 (m, 1H), 1.58-1.73(m, 1H), 3.62-3.84 (m, 1H), 3.89 (s, 3H), 7.28-7.40 (m, 2H), 7.45-7.58(m, 1H), 7.63 (d, J=1.5 Hz, 1H), 8.15 (br. s., 1H), 10.12 (br. s, 1H).

Compound 263:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[1-(trifluoromethyl)-cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 263 (154 mg) was prepared similarly as described for compound252, using 1-trifluoromethyl-cyclobutylamine instead of1,1-difluoropropan-2-amine and 48 h reaction time instead of 24 h. Anextra purification was performed via Prep HPLC (Stationary phase: RPXBridge Prep C18 OBD-10 m, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃solution in water, MeOH). Method B: Rt: 1.10 min m/z: 470.1 (M−H)⁻ Exactmass: 471.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71-1.92 (m, 2H),2.21-2.37 (m, 2H), 2.39-2.49 (m, 2H), 3.91 (s, 3H), 7.25-7.43 (m, 2H),7.46-7.58 (m, 1H), 7.62 (d, J=1.8 Hz, 1H), 8.38 (br. s., 1H), 10.16 (br.s., 1H).

Compound 264:N-(3-chloro-2,4-difluoro-phenyl)-4-{[2-fluoro-1-(fluoromethyl)-ethyl]sulfamoyl}-1-methyl-1H-pyrrole-2-carboxamide

Compound 264 (231 mg) was prepared similarly as described for compound252, using 1,3-difluoropropan-2-amine hydrochloride instead of1,1-difluoropropan-2-amine. Method B: Rt: 0.96 min m/z: 426.1 (M−H)⁻Exact mass: 427.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.53-3.75 (m, 1H),3.89 (s, 3H), 4.28-4.53 (m, 4H), 7.24-7.41 (m, 2H), 7.45-7.58 (m, 1H),7.62 (d, J=1.8 Hz, 1H), 8.04 (br. s., 1H), 10.02 (br. s, 1H).

Compound 265:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[(1R)-1-(trifluoro-methyl)propyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 265 (241 mg) was prepared similarly as described for compound252, using (R)-1,1,1-trifluoro-2-butylamine instead of1,1-difluoropropan-2-amine and 48 hours reaction time instead of 24 h.Method B: Rt: 1.09 min m/z: 458.1 (M−H)⁻ Exact mass: 459.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.73 (t, J=7.5 Hz, 3H), 1.38-1.52 (m, 1H), 1.58-1.73(m, 1H), 3.67-3.83 (m, 1H), 3.89 (s, 3H), 7.29-7.39 (m, 2H), 7.45-7.58(m, 1H), 7.63 (d, J=1.5 Hz, 1H), 8.16 (br. s., 1H), 10.13 (br. s., 1H).

Compound 266:N-(3-chloro-2,4-difluoro-phenyl)-1-methyl-4-{[3-(trifluoromethyl)-tetrahydrofuran-3-yl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 266 (140 mg) was prepared similarly as described for compound252, using 3-(trifluoromethyl)tetrahydrofuran-3-amine hydrochlorideinstead of 1,1-difluoropropan-2-amine. An extra purification wasperformed via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10μm, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, MeOH).

Method B: Rt: 1.03 min m/z: 486.1 (M−H)⁻ Exact mass: 487.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.19 (dt, J=13.8, 8.1 Hz, 1H), 2.40-2.48 (m, 1H),3.62 (q, J=7.8 Hz, 1H), 3.79-3.87 (m, 1H), 3.89 (s, 3H), 3.95 (d, J=10.1Hz, 1H), 4.01-4.11 (m, 1H), 7.27-7.41 (m, 2H), 7.49-7.57 (m, 1H), 7.60(d, J=1.8 Hz, 1H), 8.52 (br. s., 1H), 10.15 (br. s., 1H).

Compound 267:3-chloro-N-(3,4-difluorophenyl)-1-methyl-4-{[1-(trifluoromethyl)-cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Methyl3-chloro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylate(83 mg, 0.22 mmol) and 3,4-difluoroaniline (37 mg, 0.29 mmol) weredissolved in dry THF (10 mL) and cooled to 0° C. Lithiumbis(trimethylsilyl)amide (1M in THF) (0.66 mL, 1 M, 0.66 mmol) was addeddropwise and the reaction mixture was allowed to reach room temperature.The volatiles were removed under reduced pressure and the residue waspurified on silica using a heptane to EtOAc gradient and further bypreparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μm,30×150 mm, Mobile phase: 0.25% NH₄HCO₃ solution in water,CH₃CN);—resulting in compound 267 (60 mg). Method B: Rt: 1.11 min m/z:470.1 (M−H)⁻ Exact mass: 471.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74-1.91 (m, 2H), 2.24-2.36 (m, 2H),2.41-2.50 (m, 2H), 3.78 (s, 3H), 7.38-7.51 (m, 2H), 7.65 (s, 1H),7.80-7.90 (m, 1H), 8.59 (br. s., 1H), 10.55 (s, 1H).

Compound 268:3-chloro-N-(3-chloro-4-fluoro-phenyl)-1-methyl-4-{[1-(trifluoro-methyl)cyclobutyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Methyl3-chloro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylate(155 mg, 0.2 mmol) and 3-chloro-4-fluoro-aniline (38 mg, 0.26 mmol) weredissolved in dry THF (10 mL) and cooled to 0° C. Lithiumbis(trimethylsilyl)amide (1M in THF) (0.6 mL, 1 M, 0.6 mmol) was addeddropwise and the reaction mixture was allowed to reach room temperature.After 1 hour more lithium bis(trimethylsilyl)amide (1M in THF) (0.6 mL,1 M, 0.6 mmol) was added and the reaction mixture was stirred foranother hour. The volatiles were removed under reduced pressure and theresidue was purified on silica using a heptane to EtOAc gradient andfurther Preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10μm, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃ solution in water,CH₃CN)—resulting in compound 268 (23 mg). Method B: Rt: 1.17 min m/z:486.0 (M−H)⁻ Exact mass: 487.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.72-1.88 (m, 2H), 2.20-2.36 (m, 2H), 2.41-2.53 (m, 2H), 3.78 (s, 3H),7.43 (t, J=9.1 Hz, 1H), 7.58-7.69 (m, 2H), 7.99 (dd, J=6.8, 2.4 Hz, 1H),8.61 (br. s., 1H), 10.53 (s, 1H).

Compound 269:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-[(1-methylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.5 g,5.51 mmol) was dissolved in acetonitrile (8 mL) and dried on molecularsieves. NaHCO₃ (1389 mg, 16.54 mmol) was added. Isopropylamine (493.71mg, 8.27 mmol) was dissolved in acetonitrile (2 mL) and dried onmolecular sieves. The two suspensions were combined and heated at 70° C.for 2 hours. The reaction mixture was filtered and washed withacetonitrile and evaporated to dryness to afford a crude residue (1.68g). The crude was purified using silica gel column chromatography (ethylacetate in heptane from 0 to 100%) to afford methyl3-chloro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.62 g).Method D: Rt: 1.62 min m/z: 293.0 (M−H)⁻ Exact mass: 294.0. Methyl3-chloro-4-(isopropylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (500 mg,1.7 mmol) and 5-amino-2-fluorobenzonitrile (0.26 g, 1.86 mmol) weredissolved in dry THF under a blanket of nitrogen. The reaction mixturewas cooled to 0° C. and lithium bis(trimethylsilyl)amide (1M in toluene)(5.09 mL, 1 M, 5.09 mmol) was added over a period of 2 minutes. Theresulting mixture was stirred for 2 minutes while cooling was continued.The mixture was quenched with saturated ammonium chloride (50 mL) andextracted using EtOAc (2×100 mL). The combined extracts were washed withbrine (50 mL), dried on Na₂SO₄, filtered and concentrated in vacuo toafford a dark brown powder which was purified using silica gel columnchromatography (ethyl acetate in heptane from 0 to 100%) and further viaPrep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm,Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN) yielding compound269 (449 mg). Method B: Rt: 0.94 min m/z: 397.1 (M−H)⁻ Exact mass:398.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J=6.6 Hz, 6H), 3.24-3.38(m, 1H), 3.77 (s, 3H), 7.49 (br. d, J=6.8 Hz, 1H), 7.55 (t, J=9.1 Hz,1H), 7.62 (s, 1H), 7.99 (ddd, J=9.2, 4.8, 2.8 Hz, 1H), 8.20 (dd, J=5.8,2.8 Hz, 1H), 10.67 (br. s., 1H).

Compound 270:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-[(2,2,2-trifluoro-1,1-dimethylethyl)sulfamoyl]-1H-pyrrole-2-carboxamide

Compound 270 was prepared similarly as described for compound 269, using3 equiv 2,2,2-trifluoro-1,1-dimethyl-ethylamine, instead of 1.5 equivisopropylamine (heating was continued for more then 44 hours at 80° C.instead of 2 hours at 70° C.). Method B: Rt: 1.04 min m/z: 465.1 (M−H)⁻Exact mass: 466.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (s, 6H), 3.78(s, 3H), 7.56 (t, J=9.1 Hz, 1H), 7.66 (s, 1H), 7.99 (ddd, J=9.1, 4.8,2.8 Hz, 1H), 8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.34 (br. s., 1H), 10.64 (br.s., 1H).

Compound 271:3-Chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-4-{[1-(trifluoro-methyl)cyclopropyl]sulfamoyl}-1H-pyrrole-2-carboxamide

Compound 271 was prepared similarly as described for compound 270, using1-(trifluoromethyl)cyclopropanamine instead of2,2,2-trifluoro-1,1-dimethyl-ethylamine. Method B: Rt: 1.01 min m/z:463.1 (M−H)⁻ Exact mass: 464.1. Differential scanning calorimetry: From30 to 300° C. at 10° C./min: peak at 209.5° C. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.10-1.25 (m, 4H), 3.78 (s, 3H), 7.56 (t, J=9.1 Hz, 1H), 7.65 (s,1H), 7.98 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H),9.01 (br. s., 1H), 10.67 (br. s., 1H).

Compound 272:3-chloro-N-(2-cyano-4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 272 was prepared similarly as described for compound 250, using6-amino-3-fluoro-2-methyl-benzonitrile instead of 3-bromoaniline.Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 235.1° C. Method B: Rt: 1.05 min m/z: 465.1 (M−H)⁻ Exact mass:466.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 2.43 (d,J=2.2 Hz, 3H), 3.81 (s, 3H), 3.91-4.05 (m, 1H), 7.50 (dd, J=8.8, 4.8 Hz,1H), 7.59 (t, J=9.0 Hz, 1H), 7.70 (s, 1H), 8.49 (d, J=6.6 Hz, 1H), 10.44(br. s., 1H).

Compound 273:3-chloro-N-(2-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 273 was prepared similarly as described for compound 250, using2-amino-5-fluorobenzonitrile instead of 3-bromoaniline. Method D: Rt:1.82 min m/z: 451.0 (M−H)⁻ Exact mass: 452.0. Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 200.7° C. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.81 (s, 3H), 3.91-4.06(m, 1H), 7.61-7.69 (m, 2H), 7.70 (s, 1H), 7.87-7.95 (m, 1H), 8.50 (d,J=8.6 Hz, 1H), 10.49 (s, 1H).

Compound 274:3-chloro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 274 was prepared similarly as described for compound 250, using4-fluoro-3-(trifluoromethyl)aniline instead of 3-bromoaniline. Method B:Rt: 1.15 min m/z: 494.1 (M−H)⁻ Exact mass: 495.0. Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 189.8° C. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.78 (s, 3H), 3.91-4.04(m, 1H), 7.54 (t, J=9.8 Hz, 1H), 7.68 (s, 1H), 7.91-8.02 (m, 1H), 8.19(dd, J=6.4, 2.4 Hz, 1H), 8.49 (br. s., 1H), 10.67 (s, 1H).

Compound 275:3-chloro-N-(2-fluoro-6-methyl-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 275 was prepared similarly as described for compound 250, using2-fluoro-6-methylaniline instead of 3-bromoaniline. Method B: Rt: 0.99min m/z: 440.1 (M−H)⁻ Exact mass: 441.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.14-1.29 (m, 3H), 2.28 (s, 3H), 3.76 (s, 3H), 3.91-4.03 (m, 1H),7.08-7.18 (m, 2H), 7.22-7.32 (m, 1H), 7.65 (s, 1H), 8.45 (br. s., 1H),9.85 (s, 1H).

Compound 276:3-chloro-N-(3-cyano-2,4-difluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 276 was prepared similarly as described for compound 250, using3-amino-2,6-difluorobenzonitrile instead of 3-bromoaniline. Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 217.6°C. Method B: Rt: 1.03 min m/z: 469.1 (M−H)⁻ Exact mass: 470.0. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.79 (s, 3H), 3.91-4.04(m, 1H), 7.47 (dt, J=8.9, 1.5 Hz, 1H), 7.70 (s, 1H), 8.09 (td, J=9.0,6.2 Hz, 1H), 8.50 (br. s., 1H), 10.36 (br. s., 1H).

Compound 277:3-chloro-N-(2,3-dichloro-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 277 was prepared similarly as described for compound 250, using2,3-dichloro-4-fluoroaniline instead of 3-bromoaniline. Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 206.0°C. Method B: Rt: 1.20 min m/z: 496.0 (M−H)⁻ Exact mass: 495.0. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.81 (s, 3H), 3.91-4.03(m, 1H), 7.52 (t, J=8.9 Hz, 1H), 7.70 (s, 1H), 7.76 (dd, J=9.1, 5.4 Hz,1H), 8.49 (br. s., 1H), 10.08 (br. s., 1H).

Compound 278:3-chloro-N-[3-(difluoromethyl)-2,4-difluoro-phenyl]-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Diethylaminosulfur trifluoride (23.4 mL) was added to the solution of2,6-difluoro-3-nitro-benzaldehyde (18 g, 96.21 mmol) in dichloromethane(180 mL) at −78° C. under N₂ atmosphere. The mixture was stirred for 1hour and then warmed to 25° C. for 4 hours. The mixture was poured intoaqueous NaHCO₃/ice and the aqueous phase was extracted twice with ethylacetate. The combined organic layers were dried and concentrated invacuo, resulting in crude2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene (15 g).2-(difluoromethyl)-1,3-difluoro-4-nitro-benzene (10 g, 47.8 mmol) wasstirred in water (100 mL) and ethanol (100 mL). Fe (16.0 g, 286.8 mmol)and ammonium chloride (15.34 g, 286.8 mmol) were added at 0° C. Themixture was stirred at 70° C. for 2 hours, filtered off and the filtratewas concentrated in vacuo. The residue was dissolved in water (20 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine and dried over Na₂SO₄. The solvent was removed invacuo and the obtained residue was dissolved in ethyl acetate (5 mL),and then HCl/ethylacetate (2 mL) was added. The mixture was stirred at20° C. for 20 minutes. The volatiles were removed in vacuo, resulting in3-(difluoromethyl)-2,4-difluoro-aniline hydrochloride (5.1 g). Compound278 was prepared similarly as described for compound 250, using3-(difluoromethyl)-2,4-difluoro-aniline hydrochloride instead of3-bromoaniline. Differential scanning calorimetry: From 30 to 300° C. at10° C./min: peak at 189.5° C. Method B: Rt: 1.07 min m/z: 494.1 (M−H)⁻Exact mass: 495.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz,3H), 3.79 (s, 3H), 3.97 (br. s., 1H), 7.32 (t, J=9.8 Hz, 1H), 7.35 (t,J=52.0 Hz, 1H), 7.68 (s, 1H), 7.87-7.98 (m, 1H), 8.48 (br. s., 1H),10.19 (br. s., 1H).

Compound 279:3-chloro-N-[3-(difluoromethyl)-4-fluoro-phenyl]-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 279 was prepared similarly as described for compound 250, using3-(difluoromethyl)-4-fluoro-aniline instead of 3-bromoaniline.Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 190.4° C. Method B: Rt: 1.06 min m/z: 476.1 (M−H)⁻ Exact mass:477.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=6.8 Hz, 3H), 3.77 (s,3H), 3.90-4.06 (m, 1H), 7.24 (t, J=54.4 Hz, 1H), 7.39 (t, J=9.7 Hz, 1H),7.67 (s, 1H), 7.80-7.88 (m, 1H), 8.01-8.08 (m, 1H), 8.49 (d, J=7.0 Hz,1H), 10.58 (s, 1H).

Compound 280:N-(3-bromophenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 280 (344 mg) was prepared similarly as described for compound229, using 3-bromoaniline instead of 3,4-difluoroaniline. Method D: Rt:2.02 min m/z: 472.0 (M−H)⁻ Exact mass: 473.0. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.18 (d, J=7.0 Hz, 3H), 3.80 (s, 3H), 3.91-4.04 (m, 1H), 7.27-7.35(m, 2H), 7.54 (d, J=4.4 Hz, 1H), 7.59-7.65 (m, 1H), 7.96-8.01 (m, 1H),8.59 (d, J=8.6 Hz, 1H), 10.21 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 216.8° C.

Compound 281:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[1-(trifluoro-methyl)cyclopentyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of ethyl4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (302 mg, 1.04mmol), 1-(trifluoromethyl)cyclopentanamine (216 mg, 1.4 mmol) NaHCO₃(261 mg, 3.1 mmol) acetonitrile (20 mL) and molecular sieves 4A (1000mg) was refluxed overnight. The reaction mixture was filtered andconcentrated. The residue was purified by silica gel columnchromatography using a gradient from 10 to 100% EtOAc in heptane. Theproduct fractions were concentrated yielding ethyl3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclopentyl]sulfamoyl]pyrrole-2-carboxylate(60.5 mg) as a light yellow powder. Lithium bis(trimethylsilyl)amide intoluene (0.59 mL, 1 M, 0.59 mmol) was added to ethyl3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclopentyl]sulfamoyl]pyrrole-2-carboxylate(57 mg, 0.148 mmol) and 5-amino-2-fluoro-benzonitrile (26.1 mg, 0.19mmol) in THF (10 mL) at room temperature under nitrogen. The reactionmixture was stirred 1 hour, quenched with NH₄Cl (25 mL) solution,diluted with brine (25 mL) and extracted with EtOAc (50 mL). The organiclayer was dried over magnesium sulphate, filtered and concentrated. Theresidue was purified by silica gel column chromatography using agradient from 10 to 100% EtOAc in heptane. The product fractions wereconcentrated. The residue was dissolved in hot methanol (10 mL). Theproduct crystallised upon addition of water. Compound 281 (30.5 mg) wasfiltered off and dried overnight in vacuo at 50° C. Method D: Rt: 2.02min m/z: 475.3 (M−H)⁻ Exact mass: 476.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.42-1.54 (m, 2H), 1.58-1.71 (m, 2H), 1.72-1.85 (m, 2H), 2.21-2.32 (m,2H), 3.81 (s, 3H), 7.50-7.57 (m, 2H), 7.97 (ddd, J=9.2, 4.8, 2.9 Hz,1H), 8.17 (dd, J=5.8, 2.8 Hz, 1H), 8.32 (s, 1H), 10.33 (s, 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 187.0° C.

Compound 282:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Ethyl 4-chlorosulfonyl-1,5-dimethyl-pyrrole-2-carboxylate (600 mg, 2.26mmol) was dissolved in acetonitrile (4 mL), dried on molecular sievesand NaHCO₃ (569 mg, 6.77 mmol) was added.(R)-1,1,1-trifluoro-2-propylamine (766 mg, 6.77 mmol) was dissolved inacetonitrile (1 mL) and dried on molecular sieves. The two suspensionswere combined and heated at 80° C. for 4 hours. The reaction mixture wasfiltered, washed with acetonitrile and evaporated to dryness to afford ayellow sticky powder (730 mg) which was purified using silica gel columnchromatography resulting in ethyl1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(600 mg) as colorless sticky powder. Ethyl1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(402 mg, 1.17 mmol) was dissolved in HOAc (10 mL) andN-Chlorosuccinimide (156.8 mg, 1.17 mmol) was added. The reactionmixture was heated at 40° C. over weekend. The reaction mixture wasevaporated to dryness and the residue was purified using silica gelcolumn chromatography (first ethylacetate in heptane from 0 to 100%,then again using methanol in CH₂Cl₂ from 0.1 to 0.5%) to afford ethyl3-chloro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(177 mg). Method D: Rt: 1.89 min m/z: 375.3 (M−H)⁻ Exact mass: 376.0.Lithium bis(trimethylsilyl)amide in toluene (0.934 mL, 1 M, 0.934 mmol)was added to ethyl3-chloro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(88 mg, 0.234 mmol) and 5-amino-2-fluoro-benzonitrile (41.3 mg, 0.30mmol) dissolved in THF (5 mL) and stirred overnight. The reactionmixture was quenched with NH₄Cl solution (5 mL) and diluted with brine(5 mL) then extracted with EtOAc (20 mL). The organic layer was driedover magnesium sulphate, filtered and concentrated. The obtained residuewas dissolved in DMF (1 mL) and purified by silica gel columnchromatography using a gradient from 10 to 100% EtOAc in heptane. Theproduct fractions were concentrated and the residue dissolved in hotmethanol (10 mL). Water was added until crystallisation began. Compound282 (44 mg) was filtered off and dried overnight in vacuo at 50° C.Method D: Rt: 1.89 min m/z: 465.0 (M−H)⁻ Exact mass: 466.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.8 Hz, 3H), 2.49 (s, 3H), 3.64 (s, 3H),3.87-4.00 (m, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.98 (ddd, J=9.2, 4.9, 2.6Hz, 1H), 8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 10.71 (s,1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 240.0° C.

Compound 283:N-(3-cyano-4-fluoro-5-methyl-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

2-fluoro-3-methylbenzonitrile (18 g, 133 mmol) was added to a solutionof potassium nitrate (13.5 g, 133 mmol) in sulfuric acid (250 mL) cooledat 0° C., the mixture was allowed to stir at room temperature for 40minutes. The reaction mixture was poured into ice water and the paleyellow precipitate was filtered off and dried in the vacuum ovenyielding crude 2-fluoro-3-methyl-5-nitro-benzonitrile (18 g). Crude2-fluoro-3-methyl-5-nitro-benzonitrile (18 g) was stirred in MeOH (210mL) and water (70 mL). Fe powder (16.7 g) and HCl (36 mL, 5 equiv) wereadded and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was then filtered through celite and after removal oforganic solvent, the mixture was adjusted to pH 9 with saturatedsolution of sodium carbonate and extracted with CH₂Cl₂ twice. Thecombined organic layers were dried over sodium sulfate and evaporated todryness to provide an yellow oil. The crude product was purified bycolumn chromatography to provide 5-amino-2-fluoro-3-methyl-benzonitrile(5.1 g) as a pale yellow solid. Compound 283 (123 mg) was preparedsimilarly as described for compound 229, using5-amino-2-fluoro-3-methyl-benzonitrile instead of 3,4-difluoroaniline.Method D: Rt: 1.95 min m/z: 449.3 (M−H)⁻ Exact mass: 450.1. ¹H NMR (600MHz, DMSO-d₆) δ ppm 1.18 (d, J=7.0 Hz, 3H), 2.30 (d, J=1.8 Hz, 3H), 3.80(s, 3H), 3.98 (dq, J=15.2, 7.6 Hz, 1H), 7.57 (d, J=4.3 Hz, 1H), 7.87(dd, J=6.5, 2.3 Hz, 1H), 7.97 (dd, J=5.2, 2.6 Hz, 1H), 8.64 (d, J=8.7Hz, 1H), 10.31 (s, 1H). Differential scanning calorimetry: From 30 to300° C. at 10° C./min: peak at 214.8° C.

Compound 284:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1S)-1-(trifluoro-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide

Compound 284 was prepared similarly as described for compound 281 using(S)-1-trifluoromethyl-propylamine instead of1-(trifluoromethyl)cyclopentanamine. Method D: Rt: 1.92 min m/z: 449.3(M−H)⁻ Exact mass: 450.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (t, J=7.4Hz, 3H), 1.43-1.56 (m, 1H), 1.62-1.74 (m, 1H), 3.70-3.79 (m, 1H), 3.80(s, 3H), 7.50-7.57 (m, 2H), 7.94-7.99 (m, 1H), 8.17 (dd, J=5.7, 2.6 Hz,1H), 8.58 (d, J=8.6 Hz, 1H), 10.33 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 177.3° C.

Compound 285:3-fluoro-N-(4-fluorophenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 285 (105 mg) was prepared similarly as described for compound229, using 4-fluoroaniline instead of 3,4-difluoroaniline. Method D: Rt:1.87 min m/z: 410.3 (M−H)⁻ Exact mass: 411.1. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.18 (d, J=7.0 Hz, 3H), 3.80 (s, 3H), 3.91-4.03 (m, 1H), 7.14-7.22(m, 2H), 7.51 (d, J=4.4 Hz, 1H), 7.65-7.72 (m, 2H), 8.57 (d, J=8.8 Hz,1H), 10.12 (s, 1H). Differential scanning calorimetry: From 30 to 300°C. at 10° C./min: peak at 212.9° C.

Compound 286:N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 286 (130 mg) was prepared similarly as described for compound229, using 3-(difluoromethyl)-4-fluoro-aniline instead of3,4-difluoroaniline. Method D: Rt: 1.93 min m/z: 460.0 (M−H)⁻ Exactmass: 461.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.8 Hz, 3H),3.81 (s, 3H), 3.92-4.03 (m, 1H), 7.07-7.41 (m, 2H), 7.54 (d, J=4.4 Hz,1H), 7.78-7.84 (m, 1H), 8.01 (dd, J=6.3, 2.5 Hz, 1H), 8.60 (d, J=8.8 Hz,1H), 10.28 (s, 1H). Differential scanning calorimetry: From 30 to 300°C. at 10° C./min: peak at 198.8° C.

Compound 287:N-3-(difluoromethyl)-2,4-difluoro-phenyl-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 287 (80 mg) was prepared similarly as described for compound229, using 3-(difluoromethyl)-2,4-difluoro-aniline instead of3,4-difluoroaniline. Method D: Rt: 1.95 min m/z: 478.3 (M−H)⁻ Exactmass: 479.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=7.0 Hz, 3H),3.81 (s, 3H), 3.92-4.04 (m, 1H), 7.19-7.48 (m, 2H), 7.56 (d, J=4.6 Hz,1H), 7.82-7.91 (m, 1H), 8.62 (d, J=8.8 Hz, 1H), 9.84 (s, 1H).

Compound 288:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-1-(trifluoro-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide

Compound 288 was prepared similarly as described for compound 281 using(R)-1-trifluoromethyl-propylamine instead of1-(trifluoromethyl)cyclopentanamine. Method D: Rt: 1.92 min m/z: 449.0(M−H)⁻ Exact mass: 450.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (t, J=7.3Hz, 3H), 1.43-1.56 (m, 1H), 1.62-1.74 (m, 1H), 3.70-3.79 (m, 1H), 3.80(s, 3H), 7.50-7.57 (m, 2H), 7.97 (ddd, J=9.2, 4.8, 2.6 Hz, 1H), 8.17(dd, J=5.7, 2.6 Hz, 1H), 8.58 (d, J=8.6 Hz, 1H), 10.34 (s, 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 175.7° C.

Compound 289:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1S)-1-(trifluoro-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide

Methyl 3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000mg, 3.68 mmol) was dissolved in CH₃CN (18 mL) in a pressure tube andthis was dried with powdered molecular sieves (4A) over a period of 30minutes. Another tube was loaded with (S)-1-trifluoromethyl-propylamine(700.7 mg, 5.51 mmol) and NaHCO₃ (926 mg, 11.03 mmol) and this wasdispersed in acetonitrile (2 mL) and dried with powdered molecularsieves (4A) over a period of 30 minutes. This was added to the pressuretube which was flushed with nitrogen, capped and stirred in a heatingblock at 80° C. for 48 hours and next 1 hour at 125° C. by microwaveirradiation. The reaction mixture was filtered and concentrated. Theresidue was dissolved in CH₂Cl₂ (5 mL) filtered and subjected to silicagel column chromatography using a gradient from 10 to 100% EtOAc inheptane. The product fractions were concentrated yielding methyl3-chloro-1-methyl-4-[[(1S)-1-(trifluoromethyl)propyl]sulfamoyl]pyrrole-2-carboxylate(829 mg) as a white solidified resin. Lithium bis(trimethylsilyl)amidein toluene (1.844 mL, 1 M, 1.84 mmol) was added to methyl3-chloro-1-methyl-4-[[(1S)-1-(trifluoromethyl)propyl]sulfamoyl]pyrrole-2-carboxylate(167.2 mg, 0.461 mmol) and 5-amino-2-fluoro-benzonitrile (81.6 mg, 0.599mmol) dissolved in THF (2 mL) and stirred overnight. The reactionmixture was quenched with NH₄Cl solution (5 mL) and diluted with brine(5 mL) then extracted with EtOAc (20 mL). The organic layer was driedover magnesium sulphate, filtered and concentrated. The residue waspurified by column chromatography using a gradient from 10 to 100% EtOAcin heptane. The product fractions were concentrated and the residuedissolved in methanol (10 mL). Water was added until crystallisationbegan. Compound 289 (160 mg) was filtered off and dried overnight invacuo at 50° C. Method D: Rt: 1.92 min m/z: 465.0 (M−H)⁻ Exact mass:466.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (t, J=7.4 Hz, 3H), 1.46-1.59(m, 1H), 1.61-1.73 (m, 1H), 3.72-3.82 (m, 4H), 7.56 (t, J=9.1 Hz, 1H),7.66 (s, 1H), 7.99 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.20 (dd, J=5.7, 2.6Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 10.65 (s, 1H). Differential scanningcalorimetry: From 30 to 300° C. at 10° C./min: peak at 184.8° C.

Compound 290:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-1-(trifluoro-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide

Compound 290 (133 mg) was prepared similarly as described for compound289 using (R)-1,1,1-trifluoro-2-butylamine instead of(S)-1-trifluoromethyl-propylamine. Method D: Rt: 1.95 min m/z: 465.3(M−H)⁻ Exact mass: 466.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (t, J=7.4Hz, 3H), 1.45-1.59 (m, 1H), 1.61-1.73 (m, 1H), 3.71-3.82 (m, 4H), 7.56(t, J=9.1 Hz, 1H), 7.66 (s, 1H), 7.99 (ddd, J=9.2, 4.8, 2.6 Hz, 1H),8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 10.65 (s, 1H).Differential scanning calorimetry: From 30 to 300° C. at 10° C./min:peak at 183.8° C.

Compound 291:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-isopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Methyl 3-chloro-1H-pyrrole-2-carboxylate (2 g, 12.5 mmol) was dissolvedin DMF (20 mL) under N₂ atmosphere. NaH (60% dispersion in mineral oil)[(601.6 mg, 15.0 mmol) was added portion wise and the mixture wasstirred for 10 minutes at room temperature. 2-iodopropane (1.5 mL, 15.0mmol) was added dropwise and the mixture was stirred at room temperaturefor 16 hours. The mixture was quenched with water and the mixture wasextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography using gradient eluent Heptane-EtOAc;100-0->50-50. The product fractions were collected and concentrated invacuo resulting in methyl 3-chloro-1-isopropyl-pyrrole-2-carboxylate(1.2 g) as an oil. Methyl 3-chloro-1-isopropyl-pyrrole-2-carboxylate(1.2 g, 5.95 mmol) was added drop wise to chlorosulfonic acid (1.99 mL,29.9 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture waswarmed to room temperature and allowed to stir for 1 hour. The resultingmixture was added dropwise to a stirred, temperature controlledice-water mixture (100 mL) keeping the temperature under 5° C. A whitesuspension was formed. The obtained aqueous suspension was extractedusing Me-THF (2×50 mL). The combined extracts were washed with Brine anddried on sodium sulphate, filtered and concentrated in vacuo yieldingmethyl 3-chloro-4-chlorosulfonyl-1-isopropyl-pyrrole-2-carboxylate (1.7g) which was used as such in the next step. Methyl3-chloro-4-chlorosulfonyl-1-isopropyl-pyrrole-2-carboxylate (1.7 g, 5.66mmol) was dissolved in hot acetonitrile (3 mL), molecular sieves (˜0.7g) were added and the reaction mixture was stirred. In a separate vessel(R)-1,1,1-trifluoro-2-propylamine (960.7 mg, 8.5 mmol) was dissolved inacetonitrile (2 mL), molecular sieves (˜0.7 g) were added. Thissuspension was added to the reaction mixture and then NaHCO₃ (1.43 g,17.0 mmol) was added. The vessel was closed and it was stirred overnightat 80° C. The reaction mixture was filtered and the solids were washedwith acetonitrile (2×50 mL). The organic fractions were combined andconcentrated in vacuo. The mixture was concentrated and purified bysilica gel chromatography using gradient eluent heptane-EtOAc;100-0->50-50. The product fractions were combined and concentrated invacuo resulting in methyl3-chloro-1-isopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(907 mg) as a fluffy solid. Methyl3-chloro-1-isopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(450 mg, 1.194 mmol) and 5-amino-2-fluorobenzonitrile 201 mg, 1.43 mmol)was dissolved in THF (dried on molecular sieves) (10.1 mL, 124.7 mmol).lithium bis(trimethylsilyl)amide (1M in THF) (3.58 mL, 1 M, 3.583 mmol)was added drop wise and the reaction mixture was stirred for 1 hour atroom temperature. The mixture was quenched with sat. NH₄Cl-sol. Theorganic layer was separated, dried (MgSO₄), filtered and concentrated invacuo. The product was purified by silica gel chromatography usinggradient eluent Heptane-EtOAc; 100-0->50-50. The product fractions werecollected and concentrated in vacuo. The product was crystallized from2-propanol, filtered and dried under vacuum to resulting in compound 291(58 mg) as a pale yellow solid. The filtrate was concentrated in vacuoand further purified by preperative HPLC, resulting in more compound 291(247 mg). Method B: Rt: 1.10 min m/z: 479.1 (M−H)⁻ Exact mass: 480.1. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J=6.8 Hz, 3H) 1.42 (d, J=6.6 Hz,6H) 4.00-4.09 (m, 1H) 4.71 (quin, J=6.7 Hz, 1H) 7.56 (t, J=9.1 Hz, 1H)7.78 (s, 1H) 7.95-8.00 (m, 1H) 8.20 (dd, J=5.6, 2.5 Hz, 1H) 8.47 (d,J=8.6 Hz, 1H) 10.91 (s, 1H).

Compound 292:3-bromo-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Methyl 3-bromo-1-methyl-pyrrole-2-carboxylate (5 g, 22.93 mmol) wasadded drop wise to chlorosulfonic acid (13.4 g, 114.7 mmol) at 0° C. Thereaction mixture was warmed to room temperature and allowed to stir for1 hour. The resulting mixture was added dropwise to a stirred ice-watermixture (300 mL) keeping the temperature below 5° C. An off whiteprecipitation was formed. The solids were filtered and washed with water(20 mL), triturated with diisopropylether and dried in vacuum ovenovernight, resulting in methyl3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (3.9 g).

Methyl 3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (3.9 g,12.32 mmol) was dissolved in hot acetonitrile (20 mL) in a pressurevessel (100 mL), molecular sieves (10 g) were added and the reactionmixture was stirred. In a separate vessel(R)-1,1,1-trifluoro-2-propylamine (2.09 g, 18.5 mmol) was dissolved inacetonitrile (20 mL), molecular sieves (5 g) were added. This suspensionwas added to the reaction mixture and then NaHCO₃ (3.1 g, 36.96 mmol)was added. The vessel was closed and it was stirred overnight at 80° C.The reaction mixture was filtered and the volatiles were removed underreduced pressure. The residue was purified on silica using a heptane toEtOAc gradient. The fractions containing the product were evaporated todryness resulting in methyl3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methylethyl]sulfamoyl]pyrrole-2-carboxylate(4.24 g) as a white powder. Methyl3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(150 mg, 0.38 mmol) and 5-amino-2-fluorobenzonitrile (69.6 mg, 0.5 mmol)were dissolved in dry THF (5 mL). Lithium bis(trimethylsilyl)amide (1Min THF) (1.14 mL, 1 M, 1.14 mmol) was added and the reaction mixture wasstirred overnight at room temperature. The reaction mixture was quenchedwith sat. NH₄Cl (5 mL). The organic layer was removed and the aqueouslayer extracted with CH₂Cl₂ (2×5 mL). The combined organic layers wereevaporated to dryness and the residue was purified on silica using aheptane to EtOAc gradient resulting in compound 292 (146 mg) as a lightpink powder after trituration in CH₂Cl₂/diisopropylether. Method B: Rt:1.00 min m/z: 496.9 (M−H)⁻ Exact mass: 498.0. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.20 (d, J=7.0 Hz, 3H), 3.77 (s, 3H), 4.01 (br. s., 1H), 7.57 (t,J=9.1 Hz, 1H), 7.71 (s, 1H), 7.98 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.19(dd, J=5.7, 2.6 Hz, 1H), 8.44 (br. s., 1H), 10.74 (s, 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 189.2°C.

Compound 293:3-cyano-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A microwave vial was charged with compound 292 (94 mg, 0.189 mmol) andzinc cyanide (13.6 mg, 0.113 mmol) in DMF (0.8 mL). The mixture waspurged with N₂ for 5 minutes. tetrakis(triphenylphosphine)palladium(0)(10.9 mg, 0.00945 mmol) was added and the vial capped. The mixture washeated at 160° C. for 30 minutes by microwave irradiation. The mixturewas concentrated in vacuo. A purification was performed via PreperativeHPLC (Stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, Mobilephase: 0.25% NH₄HCO₃ solution in water, CH₃CN). The product fractionswere collected and concentrated in vacuo. The residue was dissolved inMeOH and concentrated again resulting in compound 293 (8.3 mg) as awhite solid. Method B: Rt: 0.97 min m/z: 442.1 (M−H)⁻ Exact mass: 443.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d, J=6.8 Hz, 3H) 3.85 (s, 3H)4.01-4.12 (m, 1H) 7.60 (t, J=9.0 Hz, 1H) 7.82 (s, 1H) 7.95 (ddd, J=9.1,4.8, 2.8 Hz, 1H) 8.19 (dd, J=5.7, 2.6 Hz, 1H) 8.80 (br. s., 1H) 11.18(br. s., 1H).

Compound 294:N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-1-methylpropy]-sulfamoyl]pyrrole-2-carboxamide

5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonylchloride (200 mg, 0.59 mmol) was dissolved in acetonitrile (6 mL) in apressure tube and this was dried with powdered molecular sieves (4A)over a period of 30 minutes. Another tube was loaded with(R)-(−)-2-aminobutane (64.2 mg, 0.88 mmol) and NaHCO₃ (245.81 mg, 2.93mmol) and this was dispersed in acetonitrile (4 mL) and dried withpowdered molecular sieves (4A) over a period of 30 minutes. This wasadded to the pressure tube which was flushed with nitrogen, capped andstirred in a heating block at 80° C. for 2 hours. Then the reactionmixture was filtered over a small path of dicalite and rinsed usingdichloromethane (50 mL). The filtrate was concentrated in vacuo and theobtained residue was purified using silica gel column chromatography(gradient elution: EtOAc-heptane 0:100 to 100:0), resulting in compound294 (136 mg).

Method B: Rt: 1.00 min m/z: 377.1 (M−H)⁻ Exact mass: 378.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.76 (t, J=7.4 Hz, 3H), 0.91-0.99 (m, 3H), 1.29-1.41(m, 2H), 3.01-3.15 (m, 1H), 3.92 (s, 3H), 7.17 (d, J=7.5 Hz, 1H), 7.35(d, J=1.8 Hz, 1H), 7.49-7.59 (m, 2H), 8.02 (ddd, J=9.2, 4.9, 2.9 Hz,1H), 8.19-8.25 (m, 1H), 10.36 (s, 1H).

Compound 295:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-1-methyl-propyl]sulfamoyl]pyrrole-2-carboxamide

Compound 295 (515 mg) was prepared similarly as described for compound289 using (S)-(+)-2-aminobutane instead of(S)-1-trifluoromethyl-propylamine, stirring at 70° C. for 2 hours forthe formation of methyl3-chloro-1-methyl-4-[[(1R)-1-methylpropyl]sulfamoyl]pyrrole-2-carboxylateinstead of 80° C. for 48 hours as described for methyl3-chloro-1-methyl-4-[[(1S)-1-(trifluoromethyl)propyl]sulfamoyl]pyrrole-2-carboxylate.Method B: Rt: 1.01 min m/z: 411.1 (M−H)⁻ Exact mass: 412.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.79 (t, J=7.4 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H),1.31-1.45 (m, 2H), 3.03-3.18 (m, 1H), 3.77 (s, 3H), 7.42 (d, J=7.9 Hz,1H), 7.55 (t, J=9.1 Hz, 1H), 7.60 (s, 1H), 7.98 (ddd, J=9.1, 4.9, 2.8Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 10.64 (br. s., 1H).

Compound 296:N-(3-cyano-4-fluoro-phenyl)-4-[(3-hydroxy-1,1-dimethyl-propyl)sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 296 was prepared similarly as described for compound 294 using3-amino-3-methylbutan-1-ol instead of (R)-(−)-2-aminobutane. Method B:Rt: 0.85 min m/z: 407.1 (M−H)⁻ Exact mass: 408.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13-1.20 (m, 6H), 1.67 (t, J=7.0 Hz, 2H), 3.48 (t, J=6.9Hz, 2H), 3.91 (s, 3H), 4.45 (br. s., 1H), 7.07 (br. s., 1H), 7.34 (d,J=2.0 Hz, 1H), 7.49-7.57 (m, 2H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1H),8.22 (dd, J=5.8, 2.8 Hz, 1H), 10.25-10.51 (m, 1H).

Synthesis of (2S)-3,3-difluorobutan-2-amine hydrochloride

(S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol),N,O-dimethyl-hydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g,308 mmol) and N,N-diisopropylethylamine (66.3 g, 513 mmol) weredissolved in DMF (500 mL) and stirred at room temperature for 16 hours.The reaction mixture was poured into water (500 mL) and the formedprecipitate was filtered off. The filter cake was washed with water (1L) and dried to give tert-butylN-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (36 g)as a white powder. tert-butylN-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (35 g,151 mmol) was dissolved in THF (500 mL) and cooled to 0° C.Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added andthe reaction mixture was stirred 16 hours at room temperature. Thereaction mixture was poured into water (100 mL) and evaporated todryness. The residue was dissolved in EtOAc, washed with water, driedover Na₂SO₄, filtered and evaporated to dryness yielding tert-butylN-[(1S)-1-methyl-2-oxo-propyl]carbamate (22 g) as a white powder. To acooled (−78° C.) solution of tert-butylN-[(1S)-1-methyl-2-oxo-propyl]carbamate (12 g, 64.1 mmol) in CH₂Cl₂ (200mL) bis(2-methoxyethyl)-aminosulfur trifluoride (18.9 g, 117.5 mmol) wasadded. The reaction mixture was allowed to warm to room temperature andstirred overnight. The reaction mixture was poured into water andextracted with CH₂Cl₂. The organic layer was washed with water, driedover Na₂SO₄, filtered and evaporated to dryness. The obtained residuewas purified by silica gel chromatography yielding tert-butylN-[(1S)-2,2-difluoro-1-methyl-propyl]carbamate (5.8 g) as a pale yellowsolid. Tert-butyl N-[(1S)-2,2-difluoro-1-methyl-propyl]carbamate (5.8 g,27.7 mmol) was dissolved in EtOAc (100 mL). HCl (g) was bubbled throughfor 30 minutes and then the volatiles were removed under reducedpressure yielding (2S)-3,3-difluorobutan-2-amine hydrochloride (3.8 g)¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.69 (br. s., 3H), 3.76-3.63 (m, 1H), 1.72(t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).

Compound 297:N-(3-cyano-4-fluoro-phenyl)-4-[[(1S)-2,2-difluoro-1-methyl-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 297 was prepared similarly as described for compound 294 using(2S)-3,3-difluorobutan-2-amine hydrochloride instead of(R)-(−)-2-aminobutane. Method D: Rt: 1.79 min m/z: 413.0 (M−H)⁻ Exactmass: 414.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (d, J=6.8 Hz, 3H),1.57 (t, J=19.1 Hz, 3H), 3.42-3.56 (m, 1H), 3.93 (s, 3H), 7.36 (d, J=1.8Hz, 1H), 7.53 (t, J=9.2 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.78 (d, J=9.0Hz, 1H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.22 (dd, J=5.8, 2.8 Hz,1H), 10.36 (s, 1H).

Synthesis of (2R)-3,3-difluorobutan-2-amine

(R)-2-((tert-butoxycarbonyl)amino)propanoic acid (30 g, 159 mmol),N,O-dimethyl-hydroxylamine hydrochloride (17.5 g, 178 mmol), HATU (74 g,195 mmol) and N,N-diisopropylethylamine (30 g, 232 mmol) were dissolvedin DMF (300 mL) and stirred at room temperature for 15 hours. Thereaction mixture was concentrated under vacuum and the residue wasdissolved in CH₂Cl₂ (500 mL) and washed with brine (3×200 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified via silica gel chromatography using petroleumether: EtOAc 2:1 as eluent yielding tert-butylN-[(1R)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (28.9g). Tert-butylN-[(1R)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate wasdissolved in THF (300 mL) and cooled to 0° C. Methylmagnesium bromide3.0 m in diethyl ether (85 mL, 255 mmol) was added drop wise and thereaction mixture was stirred 15 hours at room temperature. The reactionmixture was quenched with sat. NH₄Cl and extracted with CH₂Cl₂ (3×100mL). The combined organic layers were dried over Na₂SO₄, filtered andevaporated to dryness. The obtained residue was purified via silica gelchromatography yielding tert-butylN-[(1R)-1-methyl-2-oxo-propyl]carbamate (18.9 g). To a cooled (−78° C.)solution of tert-butyl N-[(1R)-1-methyl-2-oxo-propyl]carbamate (10 g,53.4 mmol) in CH₂Cl₂ (200 mL) bis(2-methoxyethyl)aminosulfur trifluoride(18.9 g, 117.5 mmol) was added drop wise and stirring was continued for2 hours at −78° C. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was quenchedwith sat. NaHCO₃ and extracted with EtOAc. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and evaporated todryness. The residue was purified by silica gel chromatography using agradient from petroleum ether to petroleum ether:EtOAc 1:1 yieldingtert-butyl N-[(1R)-2,2-difluoro-1-methyl-propyl]carbamate (6.77 g).Tert-butyl N-[(1R)-2,2-difluoro-1-methyl-propyl]carbamate (6.77 g) wasdissolved in EtOAc (50 mL). HCl in EtOAc was added at 0° C. and thereaction mixture was stirred for 4 hours at room temperature. The formedprecipitate was filtered off and dried under high vacuum yielding(2R)-3,3-difluorobutan-2-amine hydrochloride (3.5 g).

Compound 298:N-(3-cyano-4-fluoro-phenyl)-4-[[(1R)-2,2-difluoro-1-methyl-propyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide

Compound 298 was prepared similarly as described for compound 294 using(2R)-3,3-difluorobutan-2-amine hydrochloride instead of(R)-(−)-2-aminobutane. Method D: Rt: 1.79 min m/z: 413.0 (M−H)⁻ Exactmass: 414.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (d, J=7.0 Hz, 3H),1.57 (t, J=19.1 Hz, 3H), 3.43-3.57 (m, 1H), 3.93 (s, 3H), 7.36 (d, J=2.0Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.78 (d, J=9.0Hz, 1H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.22 (dd, J=5.8, 2.8 Hz,1H), 10.36 (s, 1H).

Compound 299:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Br₂ (510 mg, 3.191 mmol) dissolved in HOAc (20 mL) was added to ethyl3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1050 mg, 3.03 mmol) and the solution was refluxed for 1 hour. More Br₂(0.25 equiv) was added and the solution was refluxed for 1 hour more.More Br₂ (0.3 equiv) was added and the reaction mixture was allowed toreach room temperature overnight. The reaction mixture was concentratedand the obtained residue was dissolved in EtOAc (50 mL) washed withNaHCO₃ solution, dried over magnesium sulphate, filtered andconcentrated, resulting in ethyl5-bromo-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(1.19 g) as a white powder. Method D: Rt: 1.92 min m/z: 423.2 (M−H)⁻Exact mass: 424.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J=7.0 Hz,3H), 1.28 (t, J=7.2 Hz, 3H), 3.87 (s, 3H), 3.94-4.07 (m, 1H), 4.28 (q,J=7.0 Hz, 2H), 8.88 (d, J=8.8 Hz, 1H). A solution ethyl5-bromo-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(963 mg, 2.265 mmol), tetramethyltin (852.8 mg, 4.53 mmol) in DMF (7mL), was flushed with nitrogen during 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (261.7 mg, 0.226 mmol) wasadded and the reaction mixture was heated at 140° C. during 30 minutesby microwave irradiation. The reaction mixture was concentrated and theobtained residue was purified by silica gel column chromatography usinga gradient from 10 to 100% EtOAc in heptane. The product fractions wereconcentrated yielding ethyl3-fluoro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(769 mg) as a white fluffy powder. Method D: Rt: 1.89 min m/z: 359.3(M−H)⁻ Exact mass: 360.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.8Hz, 3H), 1.27 (t, J=7.2 Hz, 3H), 2.42 (s, 3H), 3.76 (s, 3H), 3.86-3.98(m, 1H), 4.26 (q, J=7.0 Hz, 2H), 8.54 (d, J=8.8 Hz, 1H). Lithiumbis(trimethylsilyl)amide in toluene (1.66 mL, 1 M, 1.66 mmol) was addedto ethyl3-fluoro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(149.6 mg, 0.415 mmol) and 5-amino-2-fluoro-benzonitrile (73.5 mg, 0.54mmol) dissolved in THF (2 mL) and stirred overnight. The reactionmixture was quenched with NH₄Cl solution (5 mL) and diluted with brine(5 mL) then extracted with EtOAc (20 mL). The organic layer was driedover magnesium sulphate, filtered and concentrated. The residue wasdissolved in DMF (1 mL) and purified by silica gel column chromatographyusing a gradient from 10 to 100% EtOAc in heptane. The product fractionswere concentrated and the residue dissolved in methanol (2 mL). Waterwas added until crystallisation began. The powder was filtered off anddried overnight in vacuo at 50° C., resulting in compound 299 (76 mg).Method D: Rt: 1.88 min m/z: 449.1 (M−H)⁻ Exact mass: 450.1. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.8 Hz, 3H), 2.44 (s, 3H), 3.70 (s, 3H),3.85-3.99 (m, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.95 (ddd, J=9.2, 4.8, 2.9Hz, 1H), 8.17 (dd, J=5.7, 2.6 Hz, 1H), 8.55 (d, J=8.8 Hz, 1H), 10.35 (s,1H). Differential scanning calorimetry: From 30 to 300° C. at 10°C./min: peak at 177.5° C.

Compound 300:5-bromo-3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 199 (1100 mg, 2.43 mmol), DMF (15 mL), N-bromosuccinimide(449.8 mg, 2.5 mmol) were stirred at room temperature for 64 hours. Thereaction mixture was poured into water (150 mL). The pink solids werefiltered, washed with water and purified using silica gel columnchromatography (ethyl acetate in heptane from 0 to 40%) resulting incompound 300 (348 mg). Method B: Rt: 1.07 min m/z: 530.9 (M−H)⁻ Exactmass: 531.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H),3.73 (s, 3H), 3.89-4.09 (m, 1H), 7.57 (t, J=9.1 Hz, 1H), 7.97 (ddd,J=9.1, 4.8, 2.8 Hz, 1H), 8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.77 (br. s.,1H), 10.88 (br. s., 1H).

Compound 301:5-bromo-N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A mixture of ethyl5-bromo-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(174 mg, 0.409 mmol), Lithium hydroxide (29.4 mg, 1.23 mmol), THF (20mL) and water (distilled, 20 mL) was stirred overnight. More LiOH wasadded (3 equiv) and the reaction mixture was stirred for 4 hours. Thereaction mixture was concentrated, the obtained residue dissolved inwater (50 mL) and the solution was neutralised with HCl (1 M in H₂O).The formed white powder was filtered off and dried in vacuo at 50° C.,resulting in5-bromo-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (111 mg). Method D: Rt: 1.05 min m/z: 397.0 (M−H)⁻ Exact mass:397.9.5-bromo-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (106.9 mg, 0.269 mmol), HATU (127.9 mg, 0.336 mmol) and5-amino-2-fluoro-benzonitrile (73.3 mg, 0.538 mmol) were dissolved inDMF (1 mL), Et₃N (0.112 mL, 0.808 mmol) was added and the reactionmixture was stirred over weekend at 55° C. The solution was subjected tosilica gel column chromatography using a gradient from 10 to 100% EtOAcin heptane. The product fractions were concentrated. The residue wasdissolved in methanol (2 mL). Water was added until crystallisationbegan. The white powder was filtered off and dried overnight in vacuo at50° C., resulting in compound 301 (54 mg). Method D: Rt: 1.99 min m/z:515.2 (M−H)⁻ Exact mass: 516.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d,J=7.0 Hz, 3H), 3.80 (s, 3H), 3.95-4.07 (m, 1H), 7.55 (t, J=9.1 Hz, 1H),7.95 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.17 (dd, J=5.7, 2.6 Hz, 1H), 8.91(d, J=8.8 Hz, 1H), 10.55 (s, 1H).

Compound 302:3-chloro-N-(3-cyano-4-fluoro-phenyl)-5-cyclopropyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 300 (130 mg, 0.24 mmol) and potassiumcyclopropyltrifluoroborate (54.3 mg, 0.37 mmol) were dissolved indimethoxyethane (1.5 mL,) and distilled water (0.4 mL). The mixture wasdegassed with N₂ for 5 minutes. Cs₂CO₃ (239 mg, 0.73 mmol) was added andthe mixture was degassed with N₂.Tetrakis(triphenylphosphine)palladium(0) (28.3 mg, 0.024 mmol) was addedand the mixture was degassed with N₂. The vial was capped and themixture was heated at 90° C. for 30 minutes under microwave irradiation,next at 120° C. for 30 minutes under microwave irradiation and at 140°C. in MW for 30 minutes under microwave irradiation. The mixture wascooled and EtOAc was added. The organic layer was separated. The waterlayer was made acidic with HCl (1M) and extracted with ethyl acetate (5mL), The combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo. The product was purified using silica gel columnchromatography using gradient eluent Heptane-EtOAc; 100-0->0-50 andfurther via preparative HPLC (Stationary phase: RP XBridge Prep C18OBD-10 μm, 30×150 mm, Mobile phase: 0.25% NH₄HCO₃ solution in water,CH₃CN), resulting in compound 302 (10 mg). Method B: Rt: 1.10 min m/z:491.0 (M−H)⁻ Exact mass: 492.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.73-0.91 (m, 2H), 1.03-1.15 (m, 2H), 1.22 (d, J=6.8 Hz, 3H), 1.72-1.83(m, 1H), 3.74 (s, 3H), 3.93-4.09 (m, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.97(ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 8.29 (br.s., 1H), 10.73 (br. s., 1H).

Compound 303:N-(3-cyano-4-fluoro-phenyl)-3-isopropyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A microwave vial was charged with methyl3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(500 mg, 1.27 mmol) and potassium isopropenyltrifluoroborate (291 mg,1.9 mmol). Toluene (6.5 mL) and distilled water, (0.65 mL) were addedand the mixture was purged with N₂ for 5 minutes. Pd(OAc)₂ (57.1 mg,0.254 mmol) and butyldi-1-adamantylphosphine (137 mg, 0.382 mmol) wereadded under N₂ and then Cs₂CO₃ (1243 mg, 3.82 mmol) was added. The vialwas capped and the mixture was heated at 110° C. for 16 hour. Themixture was cooled and Me-THF was added. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using gradienteluent Heptane-EtOAc; 100-0 to 70-30. The product fractions werecollected and concentrated in vacuo resulting in methyl3-isopropenyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(350 mg) as a semi solid. Methyl3-isopropenyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(350 mg, 0.988 mmol) was dissolved in THF (50 mL), Pd/C (10%) (158 mg)was added under N₂-atmosphere and the reaction mixture was stirred underH₂-atmosphere until 1 eq. H₂ was absorbed. The catalyst was removed byfiltration over dicalite under nitrogen atmosphere, and the solvent wasremoved in vacuo, resulting in crude methyl3-isopropyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(352 mg). Methyl3-isopropyl-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(175 mg, 0.491 mmol) and 5-amino-2-fluorobenzonitrile (89.61 mg, 0.638mmol) were dissolved in THF (3.9 mL) dried on molecular sieves. Lithiumbis(trimethylsilyl)amide (1M in THF, 1.5 mL, 1.5 mmol) was added dropwise and the reaction mixture was stirred 1 hour at room temperature.The mixture was quenched with sat. NH₄Cl-sol. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated in vacuo. Theproduct was purified by silica gel column chromatography using gradienteluent Heptane-EtOAc; 100-0 to 50-50 and further by prep HPLC(Stationary phase: RP XBridge Prep C18 OBD-10m, 30×150 mm, Mobile phase:0.25% NH₄HCO₃ solution in water, CH₃CN). The product fractions werecollected and concentrated in vacuo. The residue was dissolved in MeOHand concentrated in vacuo again resulting in compound 303 (77 mg) as alight yellow solid. Method B: Rt: 1.06 min m/z: 459.1 (M−H)⁻ Exact mass:460.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.8 Hz, 3H) 1.18-1.30(m, 6H) 3.32-3.41 (m, 1H) 3.64 (s, 3H) 3.75-3.90 (m, 1H) 7.39 (s, 1H)7.56 (t, J=9.1 Hz, 1H) 7.90-8.02 (m, 1H) 8.12-8.25 (m, 2H) 10.81 (s,1H).

Compound 304:N-(3-cyano-4-fluoro-phenyl)-5-cyclopropyl-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Nitrogen was flushed through a mixture of compound 301 (44.4 mg, 0.086mmol) potassium cyclopropyltrifluoroborate (38.3 mg, 0.26 mmol) Cs₂CO₃(84 mg, 0.26 mmol) in dimethoxyethane (2 mL) and distilled water (0.2mL) during 5 minutes. tetrakis(triphenylphosphine)palladium(0) (19.9 mg,0.0172 mmol) was added and the reaction mixture was heated at 140° C.during 30 minutes. The reaction mixture was concentrated. The residuewas dissolved in EtOAc (10 mL) and water (5 mL) The organic layer wasdried over magnesium sulphate, filtered and concentrated. The residuewas subjected to silica gel column chromatography using a gradient from10 to 100% EtOAc in heptane. The product fractions were concentrated andthe residue was dissolved in methanol (2 mL). Water was added untilcrystallisation began. The white powder was filtered off and dried invacuo at 50° C., resulting in compound 304 (21 mg). Method D: Rt: 1.98min m/z: 475.1 (M−H)⁻ Exact mass: 476.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.82-0.91 (m, 2H), 1.04-1.10 (m, 2H), 1.23 (d, J=7.0 Hz, 3H), 1.71-1.81(m, 1H), 3.81 (s, 3H), 3.90-4.03 (m, 1H), 7.54 (t, J=9.1 Hz, 1H), 7.95(ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.17 (dd, J=5.7, 2.6 Hz, 1H), 8.47 (d,J=8.4 Hz, 1H), 10.37 (s, 1H). Differential scanning calorimetry: From 30to 300° C. at 10° C./min: peak at 161.4° C.

Compound 305:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-cyclopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

A flask (250 mL) was charged with methyl3-chloro-1H-pyrrole-2-carboxylate (2 g, 12.53 mmol), cyclopropylboronicacid (2.153 g, 25.07 mmol), Na₂CO₃ (2.66 g, 25.07 mmol) indichloroethane (50 mL). 2,2′-bipyridine (1.98 g, 12.53 mmol) andcopper(II) acetate (2.3 g, 12.53 mmol) were added and the mixture wasvigourously stirred on air and heated at 70° C. for 2 hours. The mixturewas cooled and washed with water/NH₄OH. The organic layer was separated,dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography using gradient eluentHeptane-EtOAc; 100-0->70-30. The product fractions were collected andconcentrated in vacuo resulting in methyl3-chloro-1-cyclopropyl-pyrrole-2-carboxylate (1.15 g) as a yellow oil.Chlorosulfonic acid (0.46 mL, 6.91 mmol) dissolved in dichloromethane (1mL) was added to methyl 3-chloro-1-cyclopropyl-pyrrole-2-carboxylate(1.15 g, 5.76 mmol) in CH₂Cl₂ (17.7 mL, 275.9 mmol) in an ice bath andstirred 30 minutes. The reaction was further stirred at room temperaturefor 1 hour, the precipitate was filtered off washed withdiisopropylether and used as such in the next step (0.7 g after dryingin vacuo). The precipitate (0.7 g) was added to SOCl₂ (0.7 g, 2.503mmol) and the mixture was stirred at 80° C. for 30 minutes. The mixturewas cooled and stirred at room temperature for 16 hours and concentratedin vacuo. To the residue ice was added and the mixture was extractedwith Me-THF. The organic layer was separated, dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by silica gelchromatography using gradient eluent Heptane-EtOAc; 100-0->70-30. Theproduct fractions were collected and concentrated in vacuo resulting inmethyl 3-chloro-4-chlorosulfonyl-1-cyclopropyl-pyrrole-2-carboxylate(359 mg) as an oil which solidified on standing. Methyl3-chloro-4-chlorosulfonyl-1-cyclopropyl-pyrrole-2-carboxylate (359 mg,1.20 mmol) was dissolved in hot acetonitrile (3 mL), molecular sieves(about 0.7 g) were added and the reaction mixture was stirred. In aseparate vessel (R)-1,1,1-trifluoro-2-propylamine (204.2 mg, 1.81 mmol)was dissolved in acetonitrile (2 mL), molecular sieves (about 0.7 g) wasadded. This suspension was added to the reaction mixture and then NaHCO₃(303.5 mg, 3.61 mmol) was added. The vessel was closed and it wasstirred overnight at 80° C. The reaction mixture was filtered and thesolids were washed with acetonitrile (2×50 mL). The organic fractionswere combined and concentrated in vacuo. The mixture was concentratedand purified by silica gel chromatography (solid phase, 40 g) usinggradient eluent heptane-EtOAc; 100-0->50-50. The product fractions werecombined and concentrated in vacuo to resulting in methyl3-chloro-1-cyclopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(281 mg) as an oil which solidified on standing.

Methyl3-chloro-1-cyclopropyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(100 mg, 0.267 mmol) and 5-amino-2-fluorobenzonitrile (48.681 mg, 0.347mmol) were dissolved in THF (2.1 mL, 25.8 mmol). Lithiumbis(trimethylsilyl)amide (1M in THF) (0.8 mL, 1 M, 0.8 mmol) was addeddropwise at room temperature. The mixture was stirred at roomtemperature for 1 hour. The mixture was quenched with sat. NH₄Cl-sol.The organic layer was separated, dried (MgSO₄), filtered andconcentrated in vacuo. A purification was performed via Preparative HPLC(Stationary phase: RP XBridge Prep C18 OBD-10m, 30×150 mm, Mobile phase:0.25% NH₄HCO₃ solution in water, CH₃CN). The product fractions werecollected and concentrated in vacuo. The residue was dissolved in MeOHand concentrated in vacuo again to obtain compound 305 (80 mg) as awhite solid. Method B: Rt: 1.06 min m/z: 477.0 (M−H)⁻ Exact mass: 478.0.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85-1.05 (m, 4H), 1.17 (d, J=7.0 Hz,3H), 3.61-3.76 (m, 1H), 3.93-4.12 (m, 1H), 7.53-7.60 (m, 2H), 7.95-68.01 (m, 1H), 8.17-8.23 (m, 1H), 8.49 (d, J=8.6 Hz, 1H), 10.86 (s, 1H).

Compound306:3-chloro-N-(3-cyano-4-fluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide

Compound 306 (179 mg) was prepared in two steps from methyl3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate similarly asdescribed for compound 269, using 3 equiv 3-methyl-3-oxetanamine,instead of 1.5 equiv isopropylamine in the first step. Method B: Rt:0.86 min m/z: 425.1 (M−H)⁻ Exact mass: 426.1. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.53 (s, 3H), 3.77 (s, 3H), 4.15 (d, J=6.6 Hz, 2H), 4.66 (d, J=5.9Hz, 2H), 7.55 (t, J=9.1 Hz, 1H), 7.66 (s, 1H), 7.78-8.76 (m, 1H), 7.98(ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz, 1H), 10.65 (br.s., 1H).

Compound 307:3-chloro-N-(3-cyano-4-fluoro-phenyl)-4-(cyclopentylsulfamoyl)-1-methyl-pyrrole-2-carboxamide

Compound 307 (241 mg) was prepared in two steps from methyl3-chloro-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate similarly asdescribed for compound 269, using 3 equiv cyclopentylamine, instead of1.5 equiv isopropylamine in the first step. Method B: Rt: 1.05 min m/z:423.1 (M−H)⁻ Exact mass: 424.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.51 (m, 4H), 1.51-1.77 (m, 4H), 3.41-3.52 (m, 1H), 3.77 (s, 3H),7.52-7.59 (m, 2H), 7.61 (br. s, 1H), 7.91-8.07 (m, 1H), 8.14-8.27 (m,1H), 10.65 (br. s., 1H).

Compound 308:3-bromo-N-(4-fluoro-3-methyl-phenyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 308 can be prepared similarly as described for compound 292,using 4-fluoro-3-methyl-aniline instead of 5-amino-2-fluorobenzonitrile.Method B: Rt: 1.07 min m/z: 486.0 (M−H)⁻ Exact mass: 487.0. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.23 (d, J=1.8 Hz, 3H), 3.75(s, 3H), 3.93-4.07 (m, 1H), 7.13 (t, J=9.1 Hz, 1H), 7.47-7.55 (m, 1H),7.59-7.65 (m, 1H), 7.67 (s, 1H), 8.39 (br. s., 1H), 10.36 (s, 1H).

Compound 309:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-5-(methoxymethyl)-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Nitrogen was bubbled through a mixture of compound 301 (preparedsimilarly as described in the synthesis of 301, but on a larger scale,100.1 mg, 0.194 mmol) potassium trifluoro(methoxymethyl)borate (88.6 mg,0.58 mmol), Cs₂CO₃ (189.9 mg, 0.58 mmol), DME (3 mL, 29.0 mmol), water(distilled, 0.25 mL) during 5 minutes. Thentetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was addedand the reaction mixture was heated at 140° C. during 30 minutes bymicrowave irradiation. The reaction mixture was further heated bymicrowave irradiation for 60 min at 160° C. and next the reactionmixture was concentrated. The residue was dissolved in EtOAc (50 mL) andwater (50 mL) The organic layer was dried over magnesium sulphate,filtered and concentrated. The obtained residue was purified by silicagel column chromatography using a gradient from 10 till 100% EtOAc inheptane. The product fractions were concentrated and further purified byprep HPLC (Stationary phase: RP XBridge Prep C18 ODB—5 μm, 30×250 mm,Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN) yielding compound309 (20 mg) as a white powder after drying overnight in vacuo at 50° C.Method D: Rt: 1.91 min m/z: 479.1 (M−H)⁻ Exact mass: 480.1. Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 180.7°C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=7.0 Hz, 3H), 3.31 (s, 3H),3.77 (s, 3H), 3.90-4.02 (m, 1H), 4.64-4.73 (m, 2H), 7.55 (t, J=9.1 Hz,1H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.18 (dd, J=5.7, 2.6 Hz, 1H),8.69 (d, J=8.4 Hz, 1H), 10.54 (s, 1H).

Compound 310:5-cyano-N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 301 (prepared similarly as described in the synthesis of 301,but on a larger scale, 185.6 mg, 0.346 mmol), copper (I) cyanide (93.04mg, 1.04 mmol), DMF (2 mL, 25.8 mmol) was heated 110 minutes at 160° C.under microwave irradiation. This was diluted with EtOAc (50 mL) washedwith ammonia, dried over magnesium sulphate, filtered and concentrated.The residue was purified by silica gel chromatography with EtOAc/heptanegradient from 10 to 50%. The product fractions were concentrated. Theresidue was dissolved in methanol (5 mL) and the product crystallisedupon addition of water. The white powder was filtered off and driedovernight in vacuo at 50° C., resulting in compound 310 (45 mg). MethodD: Rt: 1.91 min m/z: 460.3 (M−H)⁻ Exact mass: 461.1. Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 211.4°C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (d, J=7.0 Hz, 3H), 3.94 (s, 3H),4.04-4.15 (m, 1H), 7.57 (t, J=9.1 Hz, 1H), 7.93-7.99 (m, 1H), 8.17 (dd,J=5.7, 2.6 Hz, 1H), 9.32 (d, J=8.6 Hz, 1H), 10.87 (s, 1H).

Compound 311:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-5-vinyl-pyrrole-2-carboxamide

Nitrogen was flushed through a mixture of compound 301 (preparedsimilarly as described in the synthesis of 301, but on a larger scale,446 mg, 0.87 mmol) potassium vinyltrifluoroborate (348.0 mg, 2.60 mmol),Cs₂CO₃ (846.5 mg, 2.60 mmol), DME (7 mL), water (1 mL) during 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (200.1 mg, 0.17 mmol) was addedand the reaction mixture was heated at 140° C. during 30 minutes bymicrowave irradiation. The reaction mixture was concentrated. Theobtained residue was dissolved in EtOAc (50 mL) and water (25 mL). Theorganic layer was dried over magnesium sulphate, filtered andconcentrated. The residue was subjected to silica gel columnchromatography using a gradient from 10 till 100% EtOAc in heptane. Theproduct fractions were concentrated and the obtained residue wasdissolved in methanol (10 mL). Water was added until crystallisationbegan. The white powder was filtered off and dried in vacuo at 50° C.,resulting in compound 311 (297 mg). Method D: Rt: 1.94 min m/z: 461.1(M−H)⁻ Exact mass: 462.1. Differential scanning calorimetry: From 30 to300° C. at 10° C./min: peak at 195.8° C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.17 (d, J=6.8 Hz, 3H), 3.77 (s, 3H), 3.87-3.98 (m, 1H), 5.78-5.82 (m,1H), 5.84 (s, 1H), 6.80-6.91 (m, 1H), 7.55 (t, J=9.1 Hz, 1H), 7.96 (ddd,J=9.2, 4.8, 2.6 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H), 8.66 (d, J=8.8Hz, 1H), 10.51 (s, 1H).

Compound 312:N-(2,4-difluorophenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Et₃N (0.19 mL, 1.35 mmol) was added to3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylicacid (146 mg, 0.46 mmol), HATU (218 mg, 0.57 mmol) 2,4-difluoroaniline(119.8 mg, 0.92 mmol) in DMF (1 mL, 12.92 mmol) and stirred at 65° C.overnight. The solution was directly charged on a silica gel column andpurified by column chromatography using a gradient from 10 till 100%EtOAc in heptane. The product fractions were concentrated and theresidue was crystallised from methanol (10 mL) upon addition of water.The white crystals were filtered off and dried at 50° C. overnight,resulting in compound 312 (105 mg). Method D: Rt: 1.88 min m/z: 428.0(M−H)⁻ Exact mass: 429.1. Differential scanning calorimetry: From 30 to300° C. at 10° C./min: peak at 179.4° C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.18 (d, J=7.0 Hz, 3H), 3.81 (s, 3H), 3.91-4.03 (m, 1H), 7.07-7.14 (m,1H), 7.31-7.39 (m, 1H), 7.54 (d, J=4.6 Hz, 1H), 7.63-7.72 (m, 1H), 8.59(d, J=8.8 Hz, 1H), 9.69 (s, 1H).

Compound 313:N-(3-chloro-5-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

To a solution of 3-chloro-2-fluoro-5-nitro-benzoic acid (9 g, 40.99mmol) in DMF (150 mL), HATU (31.17 g, 82.0 mmol) and DIPEA (15.89 g,123.0 mmol) were added

The reaction was stirred at room temperature for 10 minutes. NH₄Cl (3.29g, 61.5 mmol) was added and the mixture was stirred overnight. Water wasadded and the mixture was extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried and evaporated. The crudewas purified by column chromatography over silica gel (petrolether/ethyl acetate=1/1) resulting in3-chloro-2-fluoro-5-nitro-benzamide (3 g). To a solution of3-chloro-2-fluoro-5-nitro-benzamide (3 g) in CH₃CN (50 mL), POCl₃ wasadded (6.86 g, 44.74 mmol) dropwise. The mixture was stirred at 80° C.overnight. The mixture was evaporated and NaHCO₃ solution was added toadjust the pH to 7-8. CH₂Cl₂ was added and the organic layer wascollected, dried and evaporated resulting in3-chloro-2-fluoro-5-nitro-benzonitrile (1.6 g). A mixture of3-chloro-2-fluoro-5-nitro-benzonitrile (1.5 g, 7.48 mmol) in ethylacetate (40 mL) was hydrogenated at room temperature with Pd/C (0.3 g)as a catalyst. After uptake of H₂, the catalyst was filtered off and thefiltrate was evaporated. The crude compound was purified byhigh-performance liquid chromatography (Column: ADIKMA Diamonsil (2)C₁₈, 150*25*5 um, Flow rate: 35 mL/min, Mobile Phase A: Purified water(containing 0.5% HCl), Mobile Phase B: CH₃CN, Gradient: 53-83% (% B).NaHCO₃ solution was added to adjust the pH to 8. The desired fractionwas collected and the solvent was concentrated in vacuo resulting in5-amino-3-chloro-2-fluoro-benzonitrile (253 mg).

Compound 313 (118 mg) was prepared similarly as described for compound312 using 5-amino-3-chloro-2-fluoro-benzonitrile instead of2,4-difluoroaniline. Method D: Rt: 2.01 min m/z: 469.0 (M−H)⁻ Exactmass: 470.0. Differential scanning calorimetry: From 30 to 300° C. at10° C./min: peak at 205.4° C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d,J=7.0 Hz, 3H), 3.81 (s, 3H), 3.92-4.04 (m, 1H), 7.58 (d, J=4.4 Hz, 1H),8.08 (dd, J=5.1, 2.6 Hz, 1H), 8.21 (dd, J=6.7, 2.5 Hz, 1H), 8.64 (d,J=8.4 Hz, 1H), 10.40 (s, 1H).

Compound 314:5-chloro-N-(3-cyano-2,4-difluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

NCS (20.0 mg, 0.15 mmol) was added to compound 181 (synthesizedsimilarly as described for compound 181, but on a larger scale, 68 mg,0.15 mmol) acetonitrile (1 mL, 19.15 mmol) DMF (1 mL) and stirred overweekend. More NCS (0.75 eq) was added and the reaction mixture wasstirred overnight. The reaction mixture was charged directly on a silicagel column and purified using a gradient from 10 till 100% EtOAc inheptane. The product fractions were concentrated. The obtained residuewas dissolved in methanol (5 mL) and the product crystallised uponaddition of water. The white powder was filtered off and dried overnightin vacuo at 50° C., resulting in compound 314 (9.6 mg). Method B: Rt:1.05 min m/z: 486.9 (M−H)⁻ Exact mass: 488.0.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d, J=7.0 Hz, 3H), 3.80 (s, 3H),3.95-4.15 (m, 1H), 7.47 (td, J=9.0, 1.4 Hz, 1H), 8.03 (td, J=8.9, 6.2Hz, 1H), 8.96 (d, J=8.8 Hz, 1H), 10.22 (s, 1H).

Compound 315:5-bromo-N-(3-cyano-2,4-difluoro-phenyl)-3-fluoro-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Compound 181 (synthesized similarly as described for compound 181, buton a larger scale, 221 mg, 0.486 mmol) and NBS (129.9 mg, 0.73 mmol)were dissolved in DMF (1.5 mL) and acetonitrile (1.5 mL) and stirredovernight. Extra NBS (50 mg) was added and the mixture was stirred for30 minutes. The reaction mixture was subjected directly to columnchromatography on a silica gel column chromatography system using agradient from 10 till 100% EtOAc in heptane. The product fractions wereconcentrated. The residue was crystallised from methanol (10 mL) uponaddition of water. The white crystals were filtered off and driedovernight in vacuo at 50° C., resulting in compound 315 (125 mg). MethodD: Rt: 1.93 min m/z: 533.0 (M−H)⁻ Exact mass: 534.0. Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 197.6°C. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.22 (d, J=7.0 Hz, 3H), 3.81 (s, 3H),3.95-4.08 (m, 1H), 7.48 (s, 1H), 7.98-8.07 (m, 1H), 8.95 (d, J=8.8 Hz,1H), 10.28 (s, 1H).

Compound 316:3-cyano-N-(3-cyano-4-fluoro-phenyl)-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

Ethyl3-fluoro-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(211 mg, 0.59 mmol), potassium cyanide (190.9 mg, 2.93 mmol), DMA (5 mL,54.0 mmol), 18-crown-6 (156.6 mg, 0.59 mmol) were heated at 165° C.during 6 hours and further overnight at 150° C. The reaction mixture wasconcentrated. The obtained residue was dissolved in water/EtOAc (10/20mL) The organic layer was dried over magnesium sulphate, filtered andconcentrated. The obtained residue was purified by silica gel columnchromatography using a gradient from 10 till 100% EtOAc in heptane. Theproduct fractions were concentrated yielding ethyl3-cyano-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(27 mg) as a clear oil which was used as such. Method D: Rt: 1.74 minm/z: 366.0 (M−H)⁻ Exact mass: 367.1. Lithium bis(trimethylsilyl)amide intoluene (0.296 mL, 1 M, 0.296 mmol) was added to a mixture of ethyl3-cyano-1,5-dimethyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate(27 mg, 0.07 mmol) and 5-amino-2-fluoro-benzonitrile (13.1 mg, 0.10mmol) in THF (2 mL) and stirred overnight. The reaction mixture wasquenched with NH₄Cl solution (5 mL) and diluted with brine (5 mL), thenextracted with EtOAc (20 mL). The organic layer was dried over magnesiumsulphate, filtered and concentrated. The residue was dissolved in DMF (1mL) and purified by silica gel column chromatography using a gradientfrom 10 till 100% EtOAc in heptane. The product fractions wereconcentrated and the residue dissolved in methanol (2 mL). Water wasadded until crystallisation began. The crystals were filtered off anddried in vacuo at 50° C., resulting in compound 316 (8 mg). Method D:Rt: 1.78 min m/z: 456.1 (M−H)⁻ Exact mass: 457.1. ¹H NMR (360 MHz,DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3H), CH₃ overlapping DMSO signal, 3.72(s, 3H), 3.93-4.05 (m, 1H), 7.59 (t, J=9.1 Hz, 1H), 7.94 (ddd, J=9.1,4.8, 2.8 Hz, 1H), 8.20 (dd, J=5.7, 2.6 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H),11.16 (s, 1H).

Compound 317:N-(3-cyano-4-fluoro-phenyl)-4-[[(1R)-2,2-difluoro-1-methyl-propyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxamide

Ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (725 mg,2.54 mmol), (2R)-3,3-difluorobutan-2-amine hydrochloride (415.7 mg),NaHCO₃ (853 mg, 10.2 mmol), acetonitrile (10 mL) and molecular sieves 4A(3000 mg) were heated at 80° C. for 18 hours in a pressure tube. Thereaction mixture was filtered and the solids on filter were washed withacetonitrile (2×10 mL). The filtrate was concentrated. The residue (1 g)was subjected to silica gel column chromatography using a gradient from0 till 100% EtOAc in heptane. The product fractions were concentrated invacuo at 50° C. yielding ethyl4-[[(1R)-2,2-difluoro-1-methyl-propyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate(882 mg) as a white powder. Ethyl4-[[(1R)-2,2-difluoro-1-methyl-propyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate(150 mg, 0.42 mmol) and 5-amino-2-fluorobenzonitrile (75.9 mg, 0.54mmol) were dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide(1.67 mL, 1 M, 1.67 mmol) was added drop wise and the reaction mixturewas stirred at room temperature for 30 minutes. The reaction mixture wasquenched with sat. NH₄Cl (aq, 5 mL). The organic layer was removed andthe aqueous layer extracted with CH₂Cl₂ (2×5 mL). The combined organiclayers were evaporated to dryness and the residue was purified by silicagel chromatography (ethyl acetate in heptane 0 to 100% and again withethyl acetate in heptane 0 to 60%). The desired fractions wereevaporated to dryness, the resulting residue was dissolved in refluxingisopropanol (7 mL) and sonicated to afford a suspension. The whitesolids were filtered and washed with isopropanol (1 mL) to affordcompound 317 (115 mg) as off white powder. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.07 (d, J=6.8 Hz, 3H), 1.58 (t, J=19.1 Hz, 3H), 3.45-3.61 (m, 1H),3.81 (s, 3H), 7.48-7.54 (m, 1H), 7.54 (t, J=9.2 Hz, 1H), 7.96 (ddd,J=9.2, 4.9, 2.6 Hz, 1H), 8.04-8.37 (m, 1H), 8.17 (dd, J=5.7, 2.6 Hz,1H), 10.32 (br. s., 1H). Method B: Rt: 0.98 min m/z: 431.1 (M−H)⁻ Exactmass: 432.1.

Compound 318:N-(3-cyano-4-fluoro-phenyl)-4-[[(1S)-2,2-difluoro-1-methyl-propyl]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxamide

Compound 318 (111 mg) was prepared similarly as described for compound317, using (2S)-3,3-difluorobutan-2-amine hydrochloride instead of(2R)-3,3-difluorobutan-2-amine hydrochloride. Method B: Rt: 0.98 minm/z: 431.1 (M−H)⁻ Exact mass: 432.1.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.8 Hz, 3H), 1.58 (t, J=19.1Hz, 3H), 3.48-3.61 (m, 1H), 3.82 (s, 3H), 7.52 (d, J=4.6 Hz, 1H), 7.54(t, J=9.2 Hz, 1H), 7.96 (ddd, J=9.2, 4.9, 2.9 Hz, 1H), 8.10-8.28 (m,1H), 8.17 (dd, J=5.8, 2.8 Hz, 1H), 10.34 (br. s., 1H). Differentialscanning calorimetry: From 30 to 300° C. at 10° C./min: peak at 167.9°C.

Compound 319:N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxamide

A mixture ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate(640 mg, 2.20 mmol) 1-(trifluoromethyl)cyclobutan-1-amine (1710 mg,12.29 mmol), NaHCO₃ (553 mg, 6.58 mmol), acetonitrile (12.8 mL, 245.1mmol) and molecular sieves 4A (250 mg) was stirred and refluxed in totalfor 5 days (After 2 days another 4 equiv of1-(trifluoromethyl)cyclobutan-1-amine were added). The reaction mixturewas filtered while still hot. The filtrate was concentrated. and theobtained residue was purified by column chromatography by silica gelchromatography using a gradient from 10 to 100% EtOAc in heptane. Theproduct fractions were concentrated in vacuo at 50° C. yielding ethyl3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylate(631 mg) as white crystals. Method D: Rt: 1.90 min m/z: 371.3 (M−H)⁻Exact mass: 372.1. A solution of ethyl3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylate(624 mg, 1.68 mmol), LiOH (120.4 mg, 5.03 mmol) in THF (10 mL) and water(distilled, 10 mL) was stirred overnight. HCl (1M in H₂O) (5.03 mL, 1 M,5.03 mmol) was added and THF distilled off. The white precipitate wasfiltered off and dried overnight in vacuo at 50° C., resulting in3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylicacid (412 mg) Method D: Rt: 1.04 min m/z: 343.0 (M−H)⁻ Exact mass:344.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.82 (quin, J=8.1 Hz, 2H),2.26-2.35 (m, 2H), 2.39-2.48 (m, 2H), 3.82 (s, 3H), 7.53 (d, J=4.8 Hz,1H), 8.67 (s, 1H), 13.12 (br. s., 1H). Et₃N (0.23 mL, 1.62 mmol) wasadded to a mixture of3-fluoro-1-methyl-4-[[1-(trifluoromethyl)cyclobutyl]sulfamoyl]pyrrole-2-carboxylicacid (186 mg, 0.54 mmol), HATU (257. mg, 0.676 mmol) and5-amino-2-fluoro-benzonitrile (147.323 mg, 1.082 mmol) in DMF (2 mL) andthe mixture was stirred 4 hours at 65° C. The reaction mixture waspurified directly by silica gel column chromatography using a gradientfrom 10 till 100% EtOAc in heptane. The product fractions wereconcentrated in vacuo yielding a white powder which was dried overnightin vacuo at 50° C. This powder was dissolved in warm methanol (25 mL)and water was added until crystallisation began. The white crystals werefiltered off and dried in vacuo at 50° C. overnight, resulting incompound 319 (157 mg). Method D: Rt: 1.96 min m/z: 461.3 (M−H)⁻ Exactmass: 462.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78-1.91 (m, 2H),2.28-2.37 (m, 2H), 2.41-2.48 (m, 2H), 3.82 (s, 3H), 7.50-7.58 (m, 2H),7.97 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.17 (dd, J=5.8, 2.8 Hz, 1H), 8.71(s, 1H), 10.36 (s, 1H).

Biological Examples—Anti-HBV Activity of Compounds of Formula (ID)

The anti-HBV activity was measured using a stable transfected cell line,HepG2.2.15. This cell line was described to secrete relativelyconsistent high levels of HBV virion particles, which have been shown tocause both acute and chronic infection and disease in chimpanzees.

For the antiviral, assay cells were treated twice for three days withserially diluted compound in 96-well plates in duplicate. After 6 daysof treatment the antiviral activity was determined by quantification ofpurified HBV DNA from secreted virions using realtime PCR and an HBVspecific primer set and probe.

The anti HBV activity was also measured using the HepG2.117 cell line, astable, inducibly HBV producing cell line, which replicates HBV in theabsence of doxicycline (Tet-off system). For the antiviral assay, HBVreplication was induced, followed by a treatment with serially dilutedcompound in 96-well plates in duplicate. After 3 days of treatment, theantiviral activity was determined by quantification of intracellular HBVDNA using realtime PCR and an HBV specific primer set and probe.

Cytotoxicity of the compounds was tested using HepG2 cells, incubatedfor 4 days in the presence of compounds. The viability of the cells wasassessed using a Resazurin assay. Results are displayed in Table 1.

TABLE 1 HepG2 HepG2 HepG2 Co. 2.15 117 4 days No. EC₅₀ (μM) EC₅₀ (μM)CC₅₀ (μM)  1 0.42 3.10 >25  2 0.03 0.06 >25  3 0.07 0.10 >25  4 0.100.06 >25  5 0.03 0.02 >25  6 0.02 0.02 >25  7 0.12 0.10 >25  8 0.020.02 >25  9 0.01 0.03 >25  10 0.11 0.08 >25  11 0.03 0.02 >25  12 0.120.06 >25  13 0.46 0.14 >25  13a 0.35 0.20 >25  13b 1.01 0.46 >25  140.04 0.02 >25  15 0.16 0.13 >25  16 0.06 0.03 >25  17 0.03 0.02 >25  18<0.02 0.03 >25  19 0.06 0.08 >25  20 0.07 0.06 >25  21 0.22 0.84 >25  220.08 0.07 >25  23 0.02 0.13 >25  24 0.20 0.30 >25  25 0.34 0.23 >25  260.14 0.26 >25  27 0.04 0.06 >25  28 0.10 0.14 >25  29 0.15 0.21 >25  300.45 0.33 >25  31 0.13 0.39 >25  32 0.18 0.34 >25  33 0.03 0.04 >25  340.03 <0.02 >25  35 0.03 0.02 >25  36 0.08 0.04 >25  37 0.73 0.38 >25  380.05 0.02 >25  39 0.05 0.04 >25  40 0.20 0.12 >25  41 0.52 0.33 >25  420.54 0.72 >25  43 0.11 0.13 >25  44 0.37 0.26 >25  45 0.32 0.34 >25  460.12 0.17 >25  47 0.10 0.10 >25  48 0.05 0.06 >25  49 0.07 0.02 >25  500.07 0.05 >25  51 >1 >1 >25  52 0.26 0.33 >25  53 0.26 0.18 >25  54 0.200.25 >25  55 0.21 0.11 >25  56 0.02 <0.02 >25  57 0.06 0.05 >25  58 0.090.06 >25  59 0.03 0.03 >25  60 0.02 0.03 24.1  61 >1 >25  62 0.270.14 >25  63 0.06 0.04 >25  64 0.13 0.05 >25  66 0.03 0.03 >25  67 0.020.03 >25  68 0.07 0.07 >25  69 0.03 0.07 >25  70 0.02 0.04 >25  71 0.100.13 >25  72 0.01 0.01 >25  73 0.10 14.1  74 0.02 0.02 >25  75 0.180.18 >25  76 0.18 0.13 >25  77 0.07 0.18 >25  78 0.02 0.03 >25  79 0.530.46 >25  80 0.04 0.09 >25  81 0.01 0.05 >25  82 0.17 0.49 >25  83 >11.35 >25  84 0.46 0.61 >25  85 0.03 0.05 >25  86 0.37 0.35 >25  870.96 >1 >25  88 0.02 0.03 >25  89 0.02 0.02 >25  90 0.05 0.03 >25  910.06 0.04 >25  92 0.04 0.03 >25  93 0.03 0.03 >25  94 0.009 0.01 >25  950.13 0.06 >25  96 0.01 0.03 23.7  97 0.03 0.03 >25  98 0.81 0.54 >25  990.13 0.10 >25 100 0.06 0.05 12.2 101 0.03 0.03 >25 102 0.06 0.06 >25 1030.05 0.02 >25 104 0.02 0.02 >25 105 0.03 0.02 >25 106 0.01 0.01 >25 1070.01 0.01 >25 108 0.01 >25 109 0.24 0.10 >25 110 0.02 0.03 >25 111 0.0070.007 >25 112 0.06 0.09 >25 113 0.03 0.02 >25 114 0.10 0.05 >25 115 0.300.11 >25 116 0.03 0.02 >25 117 0.007 0.01 >25 118 0.05 0.02 >25 119 0.030.01 >25 120 0.03 0.03 >25 121 0.05 0.04 >25 122 0.07 >1 13.1 123 0.040.04 >25 124 0.04 0.04 >25 125 0.19 0.08 16.7 126 0.59 0.23 >25 127 0.050.19 >25 128 0.15 0.09 >25 129 0.17 0.08 >25 130 0.09 0.15 >25 131 0.010.01 >25 132 0.08 0.07 >25 133 0.04 0.08 >25 134 0.18 0.13 >25 135 0.020.26 >25 136 0.06 0.06 >25 137 0.03 0.04 16.5 138 0.10 0.03 >25 139 0.050.03 >25 140 0.10 0.06 >25 141 0.04 0.15 >25 142 0.15 0.42 >25 143 0.050.15 >25 144 0.05 0.07 >25 145 0.04 0.03 >25 146 0.07 0.04 >25 147 0.080.04 >25 148 0.11 0.07 >25 149 0.04 0.03 >25 150 0.09 0.06 >25 151 0.080.07 >25 152 0.24 0.08 >25 153 0.27 0.15 >25 154 0.13 0.08 >25 155 0.030.05 >25 156 0.04 0.03 >25 157 0.08 0.05 >25 158 0.12 0.36 >25 159 0.090.81 >25 160 0.16 0.13 >25 161 >1 0.91 >25 162 >1 0.89 >25 163 0.18 0.1114.3 164 0.13 0.13 >25 165a 0.15 0.04 9.3 165b 0.12 0.02 4.8 166 0.140.12 >25 166a 0.14 0.10 17.9 166b 0.31 0.17 21.3 167 0.12 0.31 >25 1680.12 0.32 >25 169 0.12 0.07 11.2 169a 0.14 0.05 16.1 169b 0.04 0.03 17.1170 <0.005 0.005 >100 171 0.02 0.02 >25 172 0.10 0.08 >25 173 0.210.32 >25 174 0.08 0.04 >25 175 0.07 0.13 >25 176 0.50 0.37 >25 177 0.330.26 >25 178 0.04 0.09 >25 179 0.30 0.27 >25 180 0.01 0.02 >25 181 0.0080.006 >25 182 0.01 0.03 >25 183 0.02 0.01 >25 184 0.008 0.006 >25 1850.006 0.005 >25 186 0.008 0.005 >25 187 0.008 0.006 >25 188 0.040.03 >25 189 0.007 0.007 11.3 190 0.09 0.10 >25 191 0.18 0.16 >25 1920.57 0.19 >25 193 0.14 0.11 >25 194 0.09 0.05 >25 195 0.04 0.04 >25 1960.10 0.08 >25 197 0.12 0.09 >25 198 0.15 0.08 >25 199 0.006 0.008 >25200a 0.10 0.05 >25 200b 0.09 0.10 >25 201 0.07 0.02 >25 202 0.030.02 >25 203 0.38 0.47 >25 204 0.65 0.62 >25 205 0.08 0.03 13.0 206 0.030.09 >25 207 0.05 0.14 >25 208 0.20 0.66 >25 209 0.09 0.09 >25 210 0.050.05 >25 211 0.04 0.04 >25 212 0.09 0.04 >25 213 0.21 0.31 >25 214 0.060.02 >25 215 0.02 0.010 >25 216 0.18 0.46 >25 217 0.005 0.005 >25 2180.009 0.007 >25 219 0.01 0.009 >25 220 0.10 0.04 >25 221 0.007 0.006 >25222 0.004 0.009 >25 223 0.12 0.09 >25 224 0.22 0.26 >25 225 0.070.07 >25 226 0.19 0.21 >25 227 0.02 0.04 >25 228a 0.03 0.03 >25 228b0.03 0.03 >25 229 0.004 0.004 >25 230 0.008 0.03 >25 231 0.04 0.03 >25232 0.02 0.02 >25 233 0.09 0.16 >25 234 0.02 0.03 >25 235 0.01 0.01 >25236a 0.02 0.05 >25 236b 0.06 0.05 >25 237 0.08 0.10 >25 238 0.100.11 >25 239 0.02 0.01 >25 240 0.02 0.05 >25 241 0.01 0.01 >25 242 0.200.30 >25 243 0.11 0.10 >25 244 0.14 0.53 >25 245 0.04 0.04 >25 246 0.050.06 >25 247 0.03 0.03 >25 248 0.03 0.07 >25 249 0.07 0.18 1.7 250 0.0070.40 20.0 251 0.01 0.06 >25 252 0.05 0.08 >25 253 0.01 0.01 >25 254 0.050.05 >25 255 0.09 0.10 >25 256 0.02 0.03 >25 257 0.08 0.09 >25 258 0.030.02 >25 259 0.05 0.05 >25 260 0.07 0.09 >25 261 0.04 0.13 >25 262 0.020.02 >25 263 0.005 0.008 >25 264 0.09 0.13 >25 265 0.01 0.03 >25 2660.02 0.03 >25 267 0.006 0.009 >25 268 0.005 0.006 >25 269 0.05 0.07 >25270 0.06 0.11 >25 271 0.009 0.02 >25 272 0.30 0.76 >25 273 0.42 0.70 >25274 0.02 0.04 19.4 275 0.60 0.70 >25 276 0.01 0.01 >25 277 0.03 0.04 >25278 0.006 0.01 >25 279 <0.004 0.005 >25 280 0.005 0.06 >25 281 <0.0040.007 >25 282 <0.005 0.005 >25 283 0.02 0.03 >25 284 0.009 >25 2850.007 >25 286 0.005 21.9 287 0.004 0.005 >25 288 0.007 0.01 >25 289 0.040.05 >25 290 0.02 >25 291 0.42 0.39 >25 292 0.03 15.5 293 0.02 0.05 >25294 0.04 0.10 >25 295 0.02 0.03 >25 296 0.10 0.23 >25 297 0.04 0.09 22.6298 0.02 0.05 23.7 299 0.009 >25 300 0.008 14.2 301 0.007 >25 3020.03 >25 303 >12.5 >25 304 0.01 >25 305 0.17 0.35 >25 306 0.03 0.06 >25307 0.03 >25 308 0.01 >25 309 0.53 0.32 >25 310 0.07 0.16 >25 3110.06 >25 312 0.06 >25 313 0.02 0.05 >25 314 0.007 >25 315 0.007 >25 3160.05 0.05 >25 317 0.006 >25 318 0.019 >25 319 <0.004 >25

1-15. (canceled)
 16. A compound or pharmaceutically acceptable saltthereof of formula


17. A compound or pharmaceutically acceptable salt thereof of formula


18. A compound or pharmaceutically acceptable salt thereof of formula


19. A pharmaceutical composition comprising a therapeutically effectiveamount of at least one compound as claimed in claim 1 and apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundas claimed in claim 2 and a pharmaceutically acceptable carrier.
 21. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound as claimed in claim 3 and a pharmaceuticallyacceptable carrier.
 22. A method of treating an HBV infection comprisingadministering a therapeutically effective amount of at least onecompound as claimed in claim
 1. 23. A method of treating an HBVinfection comprising administering a therapeutically effective amount ofat least one compound as claimed in claim
 2. 24. A method of treating anHBV infection comprising administering a therapeutically effectiveamount of at least one compound as claimed in claim
 3. 25. Apharmaceutical product comprising (a) a compound as claimed in claim 1and (b) an HBV inhibitor.
 26. A pharmaceutical product comprising (a) acompound as claimed in claim 2 and (b) an HBV inhibitor.
 27. Apharmaceutical product comprising (a) a compound as claimed in claim 3and (b) an HBV inhibitor.